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Secondary hyperparathyroidism (SHP) associated with chronic kidney disease (CKD) contributes to morbidity and mortality, yet the related parathyroid signaling pathways are not fully understood. Previous studies have indicated that the parathyroid mTORC1 pathway is activated in both experimental CKD and hypocalcemia-induced SHP. Furthermore, mice with parathyroid-specific mTOR deficiency (PT-mTOR -/- ) exhibit disrupted parathyroid glands, but maintain normal serum PTH levels. Conversely, PT-Tsc1 -/- mice, with mTORC1 hyperactivation, have enlarged glands and high serum PTH and calcium levels. We now uncover links between mTORC1 function, parathyroid gland morphology, and the response to CKD. Despite impaired gland structure, PT-mTOR -/- mice increased serum PTH to levels similar to controls in response to CKD, but not to acute kidney injury (AKI), highlighting the adaptability of their parathyroid glands to chronic but not acute stimulation. PT-Tsc1 -/- mice, with enlarged glands also exhibited a CKD-induced rise in serum PTH comparable to controls, but with a reduced magnitude, suggesting compromised secretion capacity. Parathyroid glands from PT-Tsc1 -/- mice displayed sustained high PTH secretion in culture, with no further increase when exposed to calcium-depleted media, unlike control glands. Complementing these findings, human data from 106 healthcare organizations demonstrated that drug-induced mTORC1 inhibition is associated with reduced serum PTH and a lower incidence of SHP in kidney transplant recipients. Collectively, our findings underscore the complex interplay between mTORC1 signaling and gland structure in the pathogenesis of SHP., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Purpose of Review: Defining the optimal parathyroid hormone (PTH) target in chronic kidney disease (CKD) is challenging, especially for bone outcomes, due to the substantial variability in the skeleton's response to PTH. Although PTH hyporesponsiveness is as integral a component of CKD-mineral bone disorder as elevated PTH levels, clinical awareness of this condition is limited. In this review, we will discuss factors and mechanisms contributing to PTH hyporesponsiveness in CKD. This knowledge may provide clues towards a personalized approach to treating secondary hyperparathyroidism in CKD., Recent Findings: Indicates a link between disturbed phosphate metabolism and impaired skeletal calcium sensing receptor signaling as an important mediator of PTH hyporesponsiveness in CKD. Further, cohort studies with diverse populations point towards differences in mineral metabolism control, rather than genetic or environmental factors, as drivers of the variability of PTH responsiveness., In Summary: Skeletal PTH hyporesponsiveness in CKD has a multifactorial origin, shows important interindividual variability, and is challenging to estimate in clinical practice. The variability in skeletal responsiveness compromises PTH as a biomarker of bone turnover, especially when considering populations that are heterogeneous in ethnicity, demography, kidney function, primary kidney disease and mineral metabolism control, and in patients treated with bone targeting drugs., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH-clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of β-catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder. Levels of both hormones increase progressively in advanced CKD and can lead to damage in multiple organs. Secondary hyperparathyroidism (SHPT), characterized by parathyroid hyperplasia with increased PTH secretion, is associated with fractures and mortality. Emerging evidence suggests that these associations may be partially explained by PTH-induced browning of adipose tissue and increased energy expenditure. Observational studies suggest a survival benefit of PTHlowering therapy, and a recent study comparing parathyroidectomy and calcimimetics further suggests the importance of intensive PTH control. The mechanisms underlying the regulation of FGF23 secretion by osteocytes in response to phosphate load have been unclear, but recent experimental studies have identified glycerol-3-phosphate, a byproduct of glycolysis released by the kidney, as a key regulator of FGF23 production. Elevated FGF23 levels have been shown to be associated with mortality, and experimental data suggest off-target adverse effects of FGF23. However, the causal role of FGF23 in adverse outcomes in CKD patients remains to be established. Further studies are needed to determine whether intensive SHPT control improves clinical outcomes and whether treatment targeting FGF23 can improve patient outcomes.

Little is known about the effect of the recently developed calcimimetic evocalcet (Evo) on parathyroid calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) expression. We examined the effects of Evo and cinacalcet (Cina) on CaSR and VDR expression in 5/6 nephrectomized Sprague-Dawley rats fed a high-phosphorus diet for 4 weeks to develop secondary hyperparathyroidism (SHPT). These uremic rats were divided into 4 groups-baseline control (Nx4W) and groups with additional treatment with either the Vehicle, Evo, or Cina for 2 weeks; normal rats were used as normal controls (NC). Blood parameters and parathyroid tissue were analyzed. CaSR and VDR expression levels were determined using immunohistochemistry. The degree of kidney injury and hyperphosphatemia was similar in the uremic groups (Nx4W, Vehicle, Cina, and Evo). Serum parathyroid hormone levels were significantly higher in the Nx4W and Vehicle groups than in the NC group. This increase was significantly suppressed in the Cina and Evo groups compared with that in the Vehicle group. Serum calcium levels were significantly and equally lower in the Cina and Evo groups relative to those in the Vehicle group. CaSR expression was significantly lower in the Nx4W and Vehicle groups than in the NC group. This downregulation was of an equally lesser magnitude in the Cina and Evo groups. A similar trend was observed for VDR expression. These results indicate that Evo and Cina treatment can increase parathyroid CaSR and VDR expression in uremic rats with SHPT, which could provide better control of mineral and bone disorder markers., (© 2023 Federation of American Societies for Experimental Biology.)

Parathyroid hormone (PTH) is secreted by the parathyroid glands (PTGs) and is an important hormone regulating mineral metabolism. Previous studies reported that high sodium diet will cause the increase in serum PTH, but the specific mechanism is unknown. Consequently, the present study aims to investigate the effects and mechanisms of high sodium on PTH synthesis and secretion from PTGs. We developed a tissue culture model using normal rat PTGs, discovered that sodium elicited and promoted concentration-dependent and time-dependent PTH secretion. Changes in sodium-associated transporters from PTGs incubated with high sodium were thoroughly examined. Increased expression of sodium-phosphate cotransporter Slc20a1 (also known as PiT-1) was observed. Further tests revealed that PiT-1 activated the NF-κB signaling pathway, resulting in increased IKKβ phosphorylation, IKBα degradation, and increased p65 phosphorylation followed by nuclear entry, which led to increased PTH transcription. Meanwhile, IKKβ phosphorylated SNAP23, promoting exocytosis and eventually led to increased PTH secretion. In conclusion, our findings indicate that PiT-1 plays an important role in the increased secretion and synthesis of PTH directly induced by high sodium under physiological conditions, and may provide a potential therapeutic target for secondary hyperparathyroidism (SHPT)., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Chief cells are the predominant cells in parathyroid glands of healthy adults; however, parathyroid oxyphil cells, whose function is unknown, increase dramatically in patients with secondary hyperparathyroidism (SHPT). Calcitriol and calcimimetics are the most powerful treatments for SHPT, while the mechanisms leading to calcitriol or calcimimetic resistance in oxyphil cell-predominant SHPT are unknown. Here we used transcriptomic and proteomic techniques to characterize oxyphil cells by comparing the differences between chief and oxyphil cell nodules of parathyroid glands in uremic patients. Compared to chief cell nodules, the most marked expression increases in oxyphil cell nodules were for mitochondrion-associated proteins. The mitochondria number and mitochondrial DNA content were also significantly increased in oxyphil cell nodules. Moreover, oxyphil cell nodules expressed parathyroid-specific factors, and exhibited lower levels of proliferation-related proteins but higher synthesis and secretion level of parathyroid hormone (PTH). The protein expression of SHPT-regulating factors, including vitamin-D receptor, calcium-sensing receptor and Klotho, were significantly downregulated in oxyphil cell nodules. Therefore, oxyphil cells characterized by enrich mitochondria in uremic patients showed higher synthesis and secretion of PTH but lower expression of SHPT regulators than chief cells, which may contribute to the pathophysiology of SHPT and the treatment resistance to calcitriol and calcimimetics., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objective: To establish an cell model of hyperparathyroidism by isolation, in vitro culture, and identification of parathyroid cells from patients with secondary hyperparathyroidism (SHPT)., Methods: The parathyroid gland tissues obtained from 10 patients with SHPT were dissociated by collagenase digestion for primary culture of the parathyroid cells. Morphological changes and growth characteristics of the cells were assessed by microscopic imaging and cell counting. The mRNA and protein expression levels of parathyroid hormone (PTH), calcium-sensing receptor (CaSR), and glial cells missing 2 (GCM2) in the primary and passaged cells were determined by immunofluorescence, qRT-PCR, and Western blotting., Results: Primary cultures of parathyroid cells were successfully obtained. The cells exhibited a high expression of PTH shown by immunofluorescence assay and had a population doubling time of approximately 71.61 h. PTH secretion in the second-passage (P2) cells was significantly lower than that in the primary (P0) and first-passage (P1) cells ( P < 0.001). Despite a significant downregulation of CaSR mRNA ( P =0.017) and protein ( P =0.006) in P1 cells as compared with P0 cells, no significant differences were found in mRNA and protein expressions of PTH or GCM2 between the two cell generations., Conclusion: Primary cultures of parathyroid cells isolated from SHPT patients by collagenase digestion show similar biological properties to the cells in vivo .

Parathyroid hormone (PTH) plays crucial role in maintaining calcium and phosphorus homeostasis. In the progression of secondary hyperparathyroidism (SHPT), expression of calcium-sensing receptors (CaSR) in the parathyroid gland decreases, which leads to persistent hypersecretion of PTH. How to precisely manipulate PTH secretion in parathyroid tissue and underlying molecular mechanism is not clear. Here, we establish an optogenetic approach that bypasses CaSR to inhibit PTH secretion in human hyperplastic parathyroid cells. We found that optogenetic stimulation elevates intracellular calcium, inhibits both PTH synthesis and secretion in human parathyroid cells. Long-term pulsatile PTH secretion induced by light stimulation prevented hyperplastic parathyroid tissue-induced bone loss by influencing the bone remodeling in mice. The effects are mediated by light stimulation of opsin expressing parathyroid cells and other type of cells in parathyroid tissue. Our study provides a strategy to regulate release of PTH and associated bone loss of SHPT through an optogenetic approach., (© 2022. The Author(s).)

Context: Sclerostin is an osteocyte-derived inhibitor of bone formation and is increased in kidney failure, but its role in the pathogenesis of renal bone disease remains unknown., Objective: We aimed to explore the association of serum sclerostin with bone metabolism in patients undergoing hemodialysis, with a particular focus on parathyroid hormone (PTH)-dependent and PTH-independent pathways., Methods: This cross-sectional and prospective cohort study included 654 patients undergoing hemodialysis at 10 facilities in Japan. We employed multivariable linear regression to explore whether sclerostin levels were associated with metacarpal bone mineral density (BMD), intact PTH, bone alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase-5b (TRACP-5b). We employed mediation analyses to explore whether and to what extent the association of PTH with bone turnover markers is mediated by sclerostin. We also compared sclerostin levels between patients with and without previous or incident fractures., Results: The median sclerostin level in hemodialysis patients was 3- to 4-fold higher than that in healthy individuals. Higher sclerostin levels were associated with higher metacarpal BMD and lower levels of intact PTH, BAP, and TRACP-5b. However, the relationships of sclerostin with bone turnover markers were substantially attenuated after adjustment for PTH. Mediation analysis suggested that the effects of PTH on bone turnover markers were mainly direct rather than mediated by sclerostin. Sclerostin levels were not associated with previous or incident fractures., Conclusion: These findings suggest that in patients undergoing dialysis, sclerostin has only a limited role in bone metabolism and may not mediate the effect of PTH on bone turnover., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To evaluate the feasibility and efficacy of total parathyroidectomy followed by modified needle-quantified injection of parathyroid autograft compared with classic incision and transplantation., Methods: We conducted a retrospective study of 171 patients with secondary hyperparathyroidism treated by hemodialysis or peritoneal dialysis. These patients were included in our study from April 2006 to December 2016, who had undergone total parathyroidectomies with autotransplantation. Patients were divided into classic incision for transplantation of parathyroid autograft group and modified needle-quantified injection group. Clinical and biochemical characteristics, including preoperative and postoperative intact parathyroid hormone levels were recorded and compared between two group patients., Results: To compare the techniques of modified needle-quantified injection and classic incision and transplantation, pre- and postoperative biochemistry and length of operation was recorded and analyzed. Preoperative biochemistry was similarly in both groups. However, autograft function achieved was significantly faster in the group with modified needle-quantified injection compared with classic incision and transplantation (P = 0.03). Median time to parathyroid function regain was 3 months for injection compared with 7 months for classic incision. There was no remarkable difference in the recurrence rates between the two groups., Conclusion: The modified needle-quantified injection of parathyroid tissue is a feasible and simple alternative to the more commonly used method of classic incision and transplantation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Because tacrolimus is predominantly metabolized by CYP3A, the blood concentration/dose (C/D) ratio is affected by CYP3A5 polymorphism. Parathyroid hormone (PTH) expression increases in secondary hyperparathyroidism, which is frequently associated with end-stage renal disease. Recently, PTH has been shown to downregulate CYP3A expression at mRNA level. In this study, we examined the influence of CYP3A5 polymorphism on and association of serum intact-PTH (iPTH) level with blood tacrolimus concentration in patients with end-stage renal disease just before kidney transplantation. Forty-eight patients who satisfied the selection criteria were analyzed. Subjects were classified into two phenotype subgroups: CYP3A5 expressor (CYP3A5*1/*1 and *1/*3; n = 15) and CYP3A5 nonexpressor (CYP3A5*3/*3; n = 33). The blood tacrolimus C/D (per body weight) ratio was significantly lower in CYP3A5 expressors than that in CYP3A5 nonexpressors. A significant positive correlation was found between tacrolimus C/D and iPTH concentrations (r = 0.305, p = 0.035), and the correlation coefficient was higher after excluding 20 patients co-administered CYP3A inhibitor or inducer (r = 0.428, p = 0.023). A multiple logistic regression analysis by stepwise selection identified CYP3A5 polymorphism and serum iPTH level as significant factors associated with tacrolimus C/D. These results may suggest the importance of dose design considering not only the CYP3A5 phenotype but also serum iPTH level when using tacrolimus in patients who undergo renal transplantation., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Secondary hyperparathyroidism (SHPT) in uremic patients is characterized by parathyroid gland (PTG) hyperplasia and parathyroid hormone (PTH) elevation. Previously, we demonstrated that NF-κB activation contributed to parathyroid cell proliferation in rats with chronic kidney disease. Although vitamin D inhibits inflammation and ameliorates SHPT, the contribution of vitamin D deficiency to SHPT via local NF-κB activation remains to be clarified. PTGs collected from 10 uremic patients with advanced SHPT were used to test the expressions of vitamin D receptor (VDR), NF-κB, and proliferating cell nuclear antigen (PCNA). Freshly excised PTG tissues were incubated for 24 hours in vitro with VDR activator (VDRA) calcitriol or NF-κB inhibitor pyrrolidine thiocarbamate (PDTC). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to investigate the regulation of PTH transcription by NF-κB. We found higher levels of activated NF-κB and lower expression of VDR in nodular hyperplastic PTGs than in diffuse hyperplasia. In cultured PTG tissues, treatment with VDRA or PDTC inhibited NF-κB activation and PCNA expression, and downregulated preproPTH mRNA and intact PTH levels. ChIP assays demonstrated the presence of NF-κB binding sites in PTH promoter. Furthermore, in luciferase reporter assays, addition of exogenous p65 significantly increased PTH luciferase activity by 2.4-fold (P < 0.01), while mutation of NF-κB binding site at position -908 of the PTH promoter suppressed p65-induced PTH reporter activity (P < 0.01). In summary, local NF-κB activation contributes to SHPT and mediates the transcriptional activation of PTH directly in uremic patients. Vitamin D deficiency may be involved in SHPT via the activation of NF-κB pathway., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hyperparathyroidism in patients on chronic hemodialysis presents with bone pain, pruritus, and extra-skeletal calcifications. Little attention has been paid to low plasma protein concentrations and muscle weakness in these patients. The present study was undertaken to characterize the impact of subtotal parathyroidectomy for chronic hemodialysis on body composition, muscle strength, plasma proteins, quality of life, and long-term clinical course., Methods: We performed a prospective observational before-after assessment study of consecutive chronic hemodialysis patients referred for parathyroidectomy. Patients were investigated at baseline before parathyroidectomy and then at 1 and 6 months after surgery, with the aim to assess changes in metabolic parameters, body composition by bioimpedance, muscle strength, and quality of life (36-items Short Form Health Survey questionnaire). Follow-up was terminated when patients reached 1 of the 3 pre-defined end points: recurrence of secondary hyperparathyroidism, transplantation, or death., Results: A group of 23 patients on hemodialysis were included. Preoperative handgrip strength was diminished by 52.4 ± 17%. After parathyroidectomy, a drop of immunoreactive parathyroid hormone concentrations (1,153 vs 237 pg/mL; P < .001) was observed together with increases in plasma protein (total: 6.8 vs7.8 g/dL, s-albumin 3.7 vs 4.4 g/dL and prealbumin: 31.7 vs 35.2 mg/dL; P < .001), handgrip strength (18.3 vs 22.9 kg: P = .001) as well as an improvement in physical dimension (32.9 vs 35.6; P = .004) and vitality (32.3 vs 47.1; P = .002) domains of the 36-items Short Form Health Survey questionnaire. After10 years, one-third of the patients had died, one-third of the patients had a recurrence of secondary hyperparathyroidism, and one-third of patients had received a kidney transplant and maintained a normal parathyroid function., Conclusion: Subtotal parathyroidectomy improves protein metabolic markers, muscle strength, and physical performance in chronic hemodialysis patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The aims of this study were to determine the rate of ectopic and supernumerary parathyroid glands and the outcome of surgical therapy in patients with refractory renal hyperparathyroidism., Materials and Methods: A retrospective review of all patients who underwent parathyroidectomy for refractory renal hyperparathyroidism was completed. Operative and pathology reports were reviewed, and the number and location of resected parathyroid glands, patient outcomes, and follow-up were determined., Results: During the period 1993-2019, a total of 68 patients underwent subtotal or total parathyroidectomy for renal hyperparathyroidism. Of those, 59 patients (87%) were on dialysis for an average of 6.7 years. We determined that 18 patients (26%) had 24 ectopic parathyroid glands, including 9 (13%) patients with 11 supernumerary glands. A total of 2 patients had a supernumerary gland in a normal anatomic location. Of the 24 ectopic glands, 14 (58%) were in the thymus. After parathyroidectomy, 4 patients (5.9%) had persistent hyperparathyroidism, 6 patients (8.8%) developed recurrent hyperparathyroidism, and 2 patients (3%) had permanent hypoparathyroidism., Conclusion: Ectopic and supernumerary parathyroid glands occurred in 26% and 16% of patients with renal hyperparathyroidism, respectively, and the thymus was the most common location. Thorough neck exploration and transcervical thymectomy are important to help reduce persistent and recurrent hyperparathyroidism after parathyroidectomy for renal hyperparathyroidism., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Secondary hyperparathyroidism (sHPT) as a result of chronic kidney disease (CKD) is a common health problem and has been reported to manifest at the sacroiliac joints (SIJ). The aim of this investigation was to systematically assess sacroiliac joint changes in asymptomatic sHPT as detected by high-resolution CT. Included in this IRB-approved retrospective case-control study were 56 patients with asymptomatic sHPT as well as 259 matched controls without SIJ disease. Demographic data were retrieved from electronic patient records. High-resolution computed tomography datasets of all patients were subjected to a structured scoring, including erosions, sclerosis, osteophytes, joint space alterations and intraarticular calcifications. Chi 2 tests were used to compare frequencies of lesions. Erosions were significantly more prevalent in patients with sHPT, and were found mainly in the ventral (28.6% vs. 13.9%; p = 0.016) and middle (17.9% vs. 7.7%; p = 0.040) iliac portions of the SIJ. Partial ankylosis was rare in both cohorts (3.6% vs. 5.0%; p > 0.999); complete ankylosis was not observed. Neither extent not prevalence of sclerosis or calcifications differed significantly between groups. Joint lesions reminiscent of sacroiliitis can be found in a substantial portion of asymptomatic patients with secondary hyperparathyroidism. Further investigations into the clinical significance of these findings are warranted.

Dear Editor,Hungry bone syndrome (HBS) is a clinico-biochemical entity characterized by the development of profound and prolonged hypocalcemia associated with hypophosphatemia, hypomagnesemia, and rising alkaline phosphatase which follows curative parathyroidectomy for severe primary and secondary hyperparathyroidism. The prevalence of HBS after parathyroidectomy in primary hyperparathyroidism (PHPT) is variable with several case series from Asia reporting remarkably higher prevalence rates of 24-87% 1., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Parathyroid hormone (PTH) regulates serum calcium levels and bone strength. Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality. In experimental SHP, the increased PTH gene expression is due to increased PTH mRNA stability and is mediated by protein-PTH mRNA interactions. Adenosine-uridine-rich binding factor 1 (AUF1) stabilizes and K-homology splicing regulatory protein (KSRP) destabilizes PTH mRNA. The peptidyl-prolyl cis/trans isomerase Pin1 acts on target proteins, including mRNA-binding proteins. Pin1 leads to KSRP dephosphorylation, but in SHP, parathyroid Pin1 activity is decreased and phosphorylated KSRP fails to bind PTH mRNA, leading to increased PTH mRNA stability and levels. A further level of post-transcriptional regulation occurs through microRNA (miRNA). Dicer mediates the final step of miRNA maturation. Parathyroid-specific Dicer knockout mice that lack miRNAs in the parathyroid develop normally. Surprisingly, these mice fail to increase serum PTH in response to both hypocalcemia and CKD, indicating that parathyroid Dicer and miRNAs are essential for stimulation of the parathyroid. Human and rodent parathyroids share similar miRNA profiles that are altered in hyperparathyroidism. The evolutionary conservation of abundant miRNAs and their regulation in hyperparathyroidism indicate their significance in parathyroid physiology and pathophysiology. let-7 and miR-148 antagonism modifies PTH secretion in vivo and in vitro, suggesting roles for specific miRNAs in parathyroid function. This review summarizes the current knowledge on the post-transcriptional mechanisms of PTH gene expression in SHP and the central contribution of miRNAs to the high serum PTH levels of both primary hyperparathyroidism and SHP., (© 2020 Federation of European Biochemical Societies.)

Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality in uremic patients. It is characterized by high serum parathyroid hormone (PTH) levels and impaired bone and mineral metabolism. The main mechanisms underlying SHP are increased PTH biosynthesis and secretion as well as increased glandular mass. The mechanisms leading to parathyroid cell proliferation in SHP are not fully understood. Reduced expressions of the receptors for calcium and vitamin D contribute to the disinhibition of parathyroid cell proliferation. Activation of transforming growth factor-α-epidermal growth factor receptor (TGF-α-EGFR), nuclear factor kappa B (NF-kB), and cyclooxygenase 2- prostaglandin E2 (Cox2-PGE2) signaling all correlate with parathyroid cell proliferation, underlining their roles in the development of SHP. In addition, the mammalian target of rapamycin (mTOR) pathway is activated in parathyroid glands of experimental SHP rats. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. Mice with parathyroid-specific deletion of all miRNAs have a muted increase in serum PTH and fail to increase parathyroid cell proliferation when challenged by CKD, suggesting that miRNA is also necessary for the development of SHP. This review summarizes the current knowledge on the mechanisms of parathyroid cell proliferation in SHP.

Purpose of Review: Hyperparathyroidism may be due to an autonomous hypersecretion of parathyroid hormone (PTH) or occurs in response to a number of physiological stimuli. A number of recent findings have provided new insights into the importance of the calcium-parathyroid-vitamin D axis to bone in normal physiology and pathological conditions., Recent Findings: PTH is known to affect bone microarchitecture with different effects on cortical and trabecular bone compartments. In trabecular bone, PTH may exert anabolic effects, whereas PTH promotes bone resorption in cortical bone. Vertebral fractures are prevalent in primary hyperparathyroidism (PHPT), and patients seem to fracture at higher values of bone mineral density (BMD) than patients with osteoporosis. This may be explained by changes in bone microarchitecture, which cannot be detected by measuring BMD. Even in mild PHPT, bone seems to benefit from parathyroidectomy. In secondary hyperparathyroidism, bone seems much more susceptible to fracture with insufficient levels of vitamin D compared with a replete vitamin status. If elevated PTH levels cannot be explained by conditions known to cause secondary hyperparathyroidism, the condition is termed normocalcemic PHPT, which also has been associated with an increased risk of fractures. Hyperparathyroidism is harmful to bone, which is why it is of importance to normalize PTH levels either by parathyroidectomy in PHPT or by counteracting conditions known to increase PTH in secondary hyperparathyroidism.

Parathyroid hormone (PTH) has an important role in the maintenance of serum calcium levels. It activates renal 1α-hydroxylase and increases the synthesis of the active form of vitamin D (1,25[OH] 2 D 3 ). PTH promotes calcium release from the bone and enhances tubular calcium resorption through direct action on these sites. Hallmarks of secondary hyperparathyroidism associated with chronic kidney disease (CKD) include increase in serum fibroblast growth factor 23 (FGF-23), reduction in renal 1,25[OH] 2 D 3 production with a decline in its serum levels, decrease in intestinal calcium absorption, and, at later stages, hyperphosphatemia and high levels of PTH. In this paper, we aim to critically discuss severe CKD-related hyperparathyroidism, in which PTH, through calcium-dependent and -independent mechanisms, leads to harmful effects and manifestations of the uremic syndrome, such as bone loss, skin and soft tissue calcification, cardiomyopathy, immunodeficiency, impairment of erythropoiesis, increase of energy expenditure, and muscle weakness., Competing Interests: The authors declare no conflict of interest.

Molecular mechanisms mediating tonic secretion of parathyroid hormone (PTH) in response to hypocalcaemia and hyperparathyroidism (HPT) are unclear. Here we demonstrate increased heterocomplex formation between the calcium-sensing receptor (CaSR) and metabotropic γ-aminobutyric acid (GABA) B 1 receptor (GABA B1 R) in hyperplastic parathyroid glands (PTGs) of patients with primary and secondary HPT. Targeted ablation of GABA B1 R or glutamic acid decarboxylase 1 and 2 in PTGs produces hypocalcaemia and hypoparathyroidism, and prevents PTH hypersecretion in PTGs cultured from mouse models of hereditary HPT and dietary calcium-deficiency. Cobinding of the CaSR/GABA B1 R complex by baclofen and high extracellular calcium blocks the coupling of heterotrimeric G-proteins to homomeric CaSRs in cultured cells and promotes PTH secretion in cultured mouse PTGs. These results combined with the ability of PTG to synthesize GABA support a critical autocrine action of GABA/GABA B1 R in mediating tonic PTH secretion of PTGs and ascribe aberrant activities of CaSR/GABA B1 R heteromer to HPT.

Possible ectopic parathyroid hormone (PTH) production in adipose tissues surrounding hyperplastic parathyroid glands was examined in patients with secondary hyperparathyroidism (SHPT). In vitro culture of adipose tissues from 31 patients excised during parathyroidectomy showed PTH secretion in 23 (74.2%) patients. In vitro PTH secretion was detected in adipose tissues adhered to the parathyroid glands from 22 (71.0%) patients, in not-adhered adipose from 11 (35.5%) and in the thymus from four (28.6%) patients. Immunohistochemistry revealed colonies of PTH- and GCM2-positive cells intricately intertwined with adipocytes in excised adipose tissues prior to culture. When pieces of parathyroid parenchyma from SHPT patients were transplanted into the thyroid of immunodeficient nude rats with induced SHPT, the transplants secreted human PTH for one to three-and-half months after transplantation and expressed adipocyte markers, PPARγ2 and perilipin A, that the transplants did not express prior to transplantation. These findings indicate the importance of thoroughly removing adipose tissues surrounding the parathyroid glands when performing parathyroidectomy. We speculate that these ectopic PTH-producing cells are parathyroid parenchymal cells pushed out from the glands along with adipocyte progenitors during nodular growth of hyperplastic parenchymal cells and that these cells proliferate in SHPT, forming colonies PTH-producing cells intricately intertwined with adipocytes.

Background: Dual phase 99mTc-sestamibi SPECT/CT preoperative parathyroid scintigraphy (PPS) is seldom discussed in terms of the transport kinetics of the tracer., Objectives: To assess the relationship between the characteristic type of tracer transport in particular PPS and histopathological findings in patients with secondary hyperparathyroidism (sHPT)., Material and Methods: The study comprised 27 patients (13 females and 14 males) with sHPT. Based on tracer accumulation in early phase (EP) and delayed phase (DP), the following types of accumulation for PPS(+) lesions were identified: EP(-)/ DP(+) (type I), EP(+)/DP(+) (type II), EP(+)/DP(-) (type III). EP(-)/DP(-) (type IV) lesions constituted PPS(-) group invisible in SPECT/CT. Overall, 69 lesions 59 PPS(+) and 10 PPS(-) were evaluated histopathologically., Results: Among SPECT/CT PPS(+), types I, II and III occurred in 9 (15%), 49 (83%), and 1 (2%) lesions, respectively. The frequency of histopathological diagnosis of normal and abnormal (APG - adenoma or hyperplasia) parathyroid gland, as well as non-parathyroid (thyroid, lymph nodes, or fat) lesions differed significantly between type I, II, and III lesions (p = 0.036). APG histopathological diagnosis was significantly more frequent in lesions with type II uptake than in lesions with type I uptake (76% vs. 33%, p = 0.0197). Type II lesions had significantly higher odds for histopathological diagnosis of APG or NPG than type IV, PPS(-) lesions [odds ratio = 13.1 (95% CI: 2.75 to 63.27)]., Conclusions: For SHP patients evaluated with SPECT/CT PPS accumulation type I is a weak premise for surgeon to find parathyroid pathology. Only persistent 99mTc-sestamibi accumulation in both phases - equivocal with accumulation type II - effectively differentiates parathyroid and non-parathyroid lesions as well as indicates with high probability the presence of adenoma or hyperplasia. Type III consistent with washout pattern is rare in sHPT.

Background/aims: Uremic tumoral calcinosis (UTC) is a rare disease with metastatic tissue calcification in maintenance hemodialysis (HD) patients. However, limited data are available on the treatment of UTC in HD patients. This article mainly discusses the diagnostic findings and efficacy of treatment on HD patients with UTC., Methods: A retrospective analysis was conducted based on the data of 13 cases of UTC, including their clinical features, biochemical indicators, imaging findings, diagnosis, therapeutic methods, and follow-up results. Parathyroidectomy (PTX) or drug treatment was determined based on intact parathyroid hormone (iPTH) levels and clinical symptoms., Results: All 13 patients were diagnosed as UTC definitely by imaging examination. The predominant areas involved were the buttocks (4 cases, 30.77%), shoulders (4 cases, 30.77%), and elbows (3 cases, 23.08%). Based on the levels of iPTH, cases were categorized into 2 different groups: PTX treatment group was associated with high levels of iPTH, while drug treatment group (lanthanum carbonate or sevelamer with sodium thiosulfate) was associated with lower iPTH levels. After PTX treatment, there was a significant decrease in serum iPTH, calcium (Ca), phosphate (P), and alkaline phosphatase levels (p < 0.05). In drug treatment group, the serum p levels were decreased significantly, along with a finding that hemoglobin levels were increased (p < 0.05). All the UTC had lessened or even disappeared after 4-6 months treatment., Conclusions: Although most UTC patients have an increased iPTH, a small number had lower iPTH levels. Based on iPTH levels and clinical symptoms, the patients were treated with PTX or drug therapy. With proper treatment, UTC disappeared without the need for surgery to remove calcinosis tissue., (© 2020 S. Karger AG, Basel.)

Background: Despite a growing population of patients starting hemodialysis in China, little is known about markers of mineral bone disease (MBD) and their management. We present data on prevalence and correlates of hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism from the China Dialysis Outcomes and Practice Patterns Study (DOPPS), with evaluation of whether these laboratory markers triggered changes in management., Methods: We compared the frequency of measurement and prevalence of poor control of MBD markers in China DOPPS with other DOPPS regions. We also used generalized estimating equations to assess correlates of MBD markers, and separate models to assess predictors of vitamin D and phosphate binder prescriptions in the China DOPPS., Results: Severe hyperphosphatemia (>7 mg/dL) and secondary hyperparathyroidism (>600 pg/mL) were common (27% and 21% prevalence, respectively); both were measured infrequently (14.9% and 3.2% of patients received monthly measurements in China). Frequency of dialysis sessions was positively associated with hyperphosphatemia; presence of residual kidney function was negatively associated with both hyperphosphatemia and secondary hyperparathyroidism. Laboratory measures indicating poor control of MBD were not associated with subsequent prescription of active vitamin D or phosphate binder., Conclusions: There are substantial opportunities for improvement and standardization of MBD management in China. Development of country-specific guidelines may yield realistic targets and standardization of medication use accounting for availability and cost.

Extracellular phosphate regulates its own renal excretion by eliciting concentration-dependent secretion of parathyroid hormone (PTH). However, the phosphate-sensing mechanism remains unknown and requires elucidation for understanding the aetiology of secondary hyperparathyroidism in chronic kidney disease (CKD). The calcium-sensing receptor (CaSR) is the main controller of PTH secretion and here we show that raising phosphate concentration within the pathophysiologic range for CKD significantly inhibits CaSR activity via non-competitive antagonism. Mutation of residue R62 in anion binding site-1 abolishes phosphate-induced inhibition of CaSR. Further, pathophysiologic phosphate concentrations elicit rapid and reversible increases in PTH secretion from freshly-isolated human parathyroid cells consistent with a receptor-mediated action. The same effect is seen in wild-type murine parathyroid glands, but not in CaSR knockout glands. By sensing moderate changes in extracellular phosphate concentration, the CaSR represents a phosphate sensor in the parathyroid gland, explaining the stimulatory effect of phosphate on PTH secretion.

The classic pathogenesis of secondary hyperparathyroidism (SHPT) began with the trade-off hypothesis based on parathyroid hormone hypersecretion brought about by renal failure resulting from a physiological response to correct metabolic disorder of calcium, phosphorus, and vitamin D. In dialysis patients with failed renal function, physiological mineral balance control by parathyroid hormone through the kidney fails and hyperparathyroidism progresses. In this process, many significant genetic findings have been established. Abnormalities of Ca-sensing receptor and vitamin D receptor are associated with the pathogenesis of SHPT, and fibroblast growth factor 23 has also been shown to be involved in the pathogenesis. Vitamin D receptor activators (VDRAs) are widely used for treatment of SHPT. However, VDRAs have calcemic and phosphatemic effects that limit their use to a subset of patients, and calcimimetics have been developed as alternative drugs for SHPT. Hyperphosphatemia also affects progression of SHPT, and control of hyperphosphatemia is, therefore, thought to be fundamental for control of SHPT. Currently, a combination of a VDRA and a calcimimetic is recognized as the optimal strategy for SHPT, and for other outcomes such as reduced cardiovascular disease and improved survival. The latest findings on the pathogenesis and treatment of SHPT are summarized in this review., (© 2018 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Objective: To compare the bone metabolism of adolescents and adults with obesity before undergoing a Roux-en-Y gastric bypass (RYGB) and 6 and 12 months after the surgery., Materials and Methods: Adolescents (G1) and adults (G2) with obesity assessed before (T0), six (T1), and 12 months after (T2) RYGB. Sun exposure, serum concentrations of 25(OH)D, calcium, phosphorous, magnesium, zinc, alkaline phosphatase, parathyroid hormone (PTH), and bone mineral density (BMD) were evaluated., Results: Sixty adolescents and 60 adults were assessed. At T0, there was no significant difference between the groups' serum 25(OH)D levels (G1 21.87 + 7.52 ng/mL, G2 21.73 + 7.60 ng/mL, p = 0.94) or sun exposure (G1 17 ± 2.0 min/day, G2 13.2 ± 5.2 min/day, p = 0.85). G1 had high levels of inadequacy of calcium (66.7%), phosphorous (80.0%), and zinc (18.3%) at T0 and had a significant fall in their 25(OH)D (p < 0.01) and magnesium (p < 0.01) levels from T1 to T2. G2 saw a significant lowering of their serum zinc levels from T0 to T1 and T2 (T1 p < 0.01; T2 p < 0.01). In both groups, there was a significant rise in PTH from T1 to T2 (G1 p = 0.04, G2 p = 0.02) and from T0 to T2 (G1 and G2 p < 0.01). In G2, 40.4% of individuals with osteopenia and osteoporosis presented inadequacy of 25(OH)D., Conclusion: RYGB was found to worsen the inadequacy of micronutrients related to bone metabolism and was associated with secondary hyperparathyroidism and low BMD values, especially among the adolescents. The irreversible damaging effects of obesity on bone metabolism can occur in adolescence.

Background: Hypercalcemia crisis is a complex disorder rarely induced by tertiary hyperparathyroidism, which clinically presents as nonsuppressible parathyroid hyperplasia with persistent increased PTH levels and hypercalcemia. It is one of the major risk factors of morbidity and mortality in end-stage renal disease. Parathyroidectomy should be in consideration in dialysis patients with severe hyperparathyroidism who are refractory to medical therapy. The implications and consequences of it, however, are not fully understood., Case Presentation: We present a case of a 70 year-old man disturbed by gastrointestinal manifestations due to hypercalcaemic crisis. The patient had longstanding hypercalcaemia and hyperparathyrodism refractory to calcimimetics, calcitonin, hormone and haemodialysis. A ectopic parathyroid gland in anterior mediastinum was found and elucidated by Tc-99 m scan. Futhermore, a video-assisted thoracoscopic parathyroidectomy was performed. Histologically, the tumour consisted of densely arranged chief cells immunohistochemically positive for PTH antigens. Consequently, calcium and parathormone were declining stably without any complications., Conclusions: On account of refractory hypercalcemia and hyperparathyroidism, radionuclide scanning is useful in the diagnosis of ectopic parathyroid gland. it is of great significance for multidisciplinary therapy combing anesthesia, surgical, endocrinology and nephrology staff.

Parathyroidectomy is useful for the treatment of secondary hyperparathyroidism (SHPT) caused by chronic renal failure. The following three types of parathyroidectomy can be performed: subtotal parathyroidectomy, total parathyroidectomy and total parathyroidectomy plus autologous transplantation (tPTX+AT). Each of the three types of surgery has advantages and disadvantages. The present study retrospectively analyzed the efficacy of tPTX+AT for the treatment of SHPT over 1 year. Thirty-seven patients who were diagnosed with secondary nephrogenic hyperparathyroidism and treated with tPTX+AT were selected between September 2014 and October 2016 and followed up for 1 year. Their average age was 66.5±46.0 years, and the average time of dialysis was 48.1±8.2 months. The patients' conditions, including the levels of intact parathyroid hormone (iPTH) and bone metabolism, were compared preoperatively and 1 and 7 days and 1, 3, 6 and 12 months after surgery. In addition, the postoperative complications, pathological data, SHPT recurrence and prognosis were examined. The results showed that the postoperative level of ostalgia and cutaneous pruritus significantly decreased in the patients. An inspection of the parathyroid tissues during the operation confirmed the presence of parathyroid gland hyperplasia with no carcinoma detected. Three patients with hoarseness recovered within 1 month, and 1 patient with unilateral recurrent laryngeal nerve injury improved after 6 months of voice training. Compared to the preoperative condition, the postoperative serum iPTH, serum calcium and serum phosphate levels were significantly decreased (P<0.001), and these differences remained significant 12 months after surgery. Compared to the preoperative condition, the alkaline phosphatase (ALP) concentration was decreased on postoperative day 1 (P<0.05), but no differences were observed on day 7 or at 1 month (P>0.05). The ALP levels continuously decreased at 3, 6 and 12 months (P<0.01). In conclusion, tPTX+AT significantly improves the quality of life and serum biomarker levels of these patients. The convenient surgical removal of the hyperplastic parathyroid gland for postoperative recurrence supports tPTX+AT as the recommended treatment for relevant patients.

Secondary hyperparathyroidism is a complication of chronic kidney disease that compromises skeletal integrity. In patients with secondary hyperparathyroidism undergoing parathyroidectomy, parathyroid hormone levels dramatically decrease. The effects of parathyroidectomy on bone tissue are poorly understood, especially regarding the proteins expressed by osteocytes, such as fibroblast growth factor 23, dentin matrix protein 1, matrix extracellular phosphoglycoprotein, sclerostin, receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin, which regulate bone turnover. The objective of this study was to characterize the bone expression of these proteins by immunohistochemistry and correlate these results with those of bone histomorphometry before and after parathyroidectomy. We studied bone biopsies that were obtained from 23 patients before and 12 months after parathyroidectomy. We observed an improvement in bone microarchitecture, but impaired mineralization after parathyroidectomy. We found significant increases in sclerostin and osteoprotegerin expression and a decrease in the RANKL/osteoprotegerin ratio after parathyroidectomy, suggesting that their expression is regulated by parathormone. These proteins correlated with structural and bone formation parameters. We conclude that after parathyroidectomy, significant changes occur in the bone expression of osteocyte proteins and that these proteins potentially regulate bone remodeling., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Altered parathyroid gland biology in patients with chronic kidney disease (CKD) is a major contributor to chronic kidney disease-mineral bone disorder (CKD-MBD). This disorder is associated with an increased risk of bone disorders, vascular calcification, and cardiovascular events. Parathyroid hormone (PTH) secretion is primarily regulated by the ionized calcium concentration as well as the phosphate concentration in the extracellular fluid and vitamin D. The metabolic disturbances in patients with CKD lead to alterations in the parathyroid gland biology. A hallmark of CKD is secondary hyperparathyroidism, characterized by an increased production and release of PTH, reduced expression of calcium-sensing and vitamin D receptors on the surface of parathyroid cells, and hyperplasia and hypertrophy of these cells. These alterations happen on different timescales and influence each other, thereby triggering a cascade of negative and positive feedback loops in a highly complex manner. Due to this complexity, mathematical models are a useful tool to break down the patterns of the multidimensional cascade of processes enabling the detailed study of subsystems. Here, we introduce a comprehensive mathematical model that includes the major adaptive mechanisms governing the production, secretion, and degradation of PTH in patients with CKD on hemodialysis. Combined with models for medications targeting the parathyroid gland, it provides a ready-to-use tool to explore treatment strategies. While the model is of particular interest for use in hemodialysis patients with secondary hyperparathyroidism, it has the potential to be applicable to other clinical scenarios such as primary hyperparathyroidism or hypo- and hypercalcemia., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: Secondary hyperparathyroidism (SHPT) in patients with end-stage renal disease (ESRD) is characterized by hyperplasia of the parathyroid glands (PTGs), while the underlying mechanism is not completely understood. Previously we demonstrated a relationship between cyclooxygenase 2 (COX2) overexpression and parathyroid hyperplasia and here we investigate the role of COX2 downstream metabolic product prostaglandin E2 (PGE2) and its receptor EP2 in the pathogenesis of SHPT., Methods: PTGs isolated from ESRD patients with advanced SHPT were used to test the expression of COX2-microsomal prostaglandin E synthase-1 (mPGES-1)-EP2 pathway. A diffuse proliferative section of the PTGs was used for tissue culture and treated with high phosphate (HPi) medium, COX2-PGE2-EP2 pathway inhibitors or agonists. EP2 short hairpin RNA (shRNA) lentivirus was locally applied to treat an SHPT rat model., Results: In PTGs isolated from ESRD patients, enhanced immunoactivities of COX2, mPGES-1 and EP2 were observed. In primary cultured PTG tissues, HPi induced intact parathyroid hormone (iPTH) secretion, proliferating cell nuclear antigen (PCNA) expression and COX2 activity, while COX2 and EP2 inhibitors attenuated hyperparathyroidism promoted by HPi. Furthermore, PGE2 or EP2 agonist (butaprost) directly stimulated hyperparathyroidism, whereas EP2 receptor antagonist or cyclic adenosine monophosphate inhibitor attenuated the hyperparathyroidism promoted by PGE2 or butaprost. EP2 shRNA treatment significantly reduced excessive expressions of EP2 and PCNA in the PTGs of nephrectomy rats fed an HPi diet, diminished the size of PTGs and downregulated serum iPTH levels., Conclusions: The COX2 downstream PGE2 and its receptor EP2 may play an important role in HPi-induced parathyroid hyperplasia and may serve as a potential therapeutic target for SHPT in ESRD., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Fibroblast growth factor 23 (FGF23) plays a key role in the complex network between the bones and other organs. Initially, it was thought that FGF23 exclusively regulated phosphate and vitamin D metabolism; however, recent research has demonstrated that an excess of FGF23 has other effects that may be detrimental in some cases. The understanding of the signaling pathways through which FGF23 acts in different organs is crucial to develop strategies aiming to prevent the negative effects associated with high FGF23 levels. FGF23 has been described to have effects on the heart, promoting left ventricular hypertrophy (LVH); the liver, leading to production of inflammatory cytokines; the bones, inhibiting mineralization; and the bone marrow, by reducing the production of erythropoietin (EPO). The identification of FGF23 receptors will play a remarkable role in future research since its selective blockade might reduce the adverse effects of FGF23. Patients with chronic kidney disease (CKD) have very high levels of FGF23 and may be the population suffering from the most adverse FGF23-related effects. The general population, as well as kidney transplant recipients, may also be affected by high FGF23. Whether the association between FGF23 and clinical events is causal or casual remains controversial. The hypothesis that FGF23 could be considered a therapeutic target is gaining relevance and may become a promising field of investigation in the future.

Etelcalcetide hydrochloride (Parsabiv ® , ONO-5163/AMG 416) is an allosteric modulator of the calcium (Ca)-sensing receptor that was originally produced by KAI Pharmaceuticals Inc. (now Amgen Inc.). It has recently been approved as the first intravenous calcimimetic agent for secondary hyperparathyroidism (SHPT) in many countries. Etelcalcetide is an intravenous injectable drug that can be administered and eliminated through the dialysis circuit in chronic kidney disease patients. In the present study, we evaluated the in vitro pharmacological profile and in vivo parathyroid hormone (PTH)- and Ca-lowering activities of etelcalcetide in a rat 5/6 nephrectomy model of chronic renal insufficiency with SHPT. Etelcalcetide increased the intracellular Ca concentration in HEK-293T cells expressing human Ca-sensing receptor with an EC 50 value (95% confidence interval) of 0.53 μM (0.28-1.0 μM) and suppressed PTH secretion from rat parathyroid gland cells with 0.36 μM (0.24-0.54 μM) by activating Ca-sensing receptor. The specificity of etelcalcetide was evaluated by examining its ability to stimulate or inhibit radioligand binding to a panel of 34 off-target proteins. There were no significant changes in the presence of 10 μM etelcalcetide. Furthermore, in a rat 5/6 nephrectomy model of chronic renal insufficiency with SHPT, single intravenous administration of etelcalcetide at 0.3, 1.0, and 3.0 mg/kg decreased plasma PTH and serum Ca levels. Taken together, the present findings identify etelcalcetide as a calcimimetic with potent PTH- and Ca-lowering effects via Ca-sensing receptor agonist activity., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Secondary hyperparathyroidism (SHP) is a frequent complication of kidney diseases. At variance with all the other forms of SHP, which are compensatory conditions, renal SHP has many pathogenetic peculiarities, which have been only in part defined. Furthermore, in the long course of chronic kidney diseases (CKD), SHP sometimes transforms into a hypercalcemic condition resembling the autonomous form of hyperparathyroidism (tertiary hyperparathyroidism; THP). The clinical consequences of SHP in CKD patients are manifold, encompassing not only bone and mineral disorders, but also other metabolic and organic changes which frequently burden these patients. Although the medical therapeutic tools have substantially increased in number and improved in their efficacy in recent decades, we have as yet no demonstration of a clear benefit regarding the major clinical outcomes. Furthermore, some of these patients, particularly when the autonomous THP develops, still require a surgical approach., (© 2019 S. Karger AG, Basel.)

Background/aims: Chronic kidney disease-mineral bone disorder is a major complication affecting the vast majority of chronic kidney disease patients. A hallmark of the disorder is an altered parathyroid gland biology resulting in secondary hyperparathyroidism. This condition is widely treated by calcimimetics like cinacalcet which act by allosteric activation of the calcium sensing receptor., Methods: Here, we present a linear multi-compartment model based on physiological principles such as first-pass metabolism and protein binding, which captures all relevant pharmacokinetic parameters of cinacalcet., Results: Due to the linear structure of the model, simulations are numerically stable and allow fast and accurate short or long-term predictions of cinacalcet concentrations in the body., Conclusion: The model compartments are physiological meaningful and can be easily adjusted to various conditions like impaired hepatic clearance or different drug administration regimens. Moreover, the model can be easily adapted to specific patient groups., Competing Interests: Peter Kotanko holds stock in Fresenius Medical Care. The other authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Background: Secondary hyperparathyroidism is characterized by parathyroid gland (PG) hyperplasia, and excessive synthesis and secretion of parathyroid hormone (PTH). Reduced vitamin D receptor (VDR) density has shown to play an essential role in PG hyperplasia progression; nevertheless, its exact mechanism remains unclear. VDR has shown to suppress the inflammation mediator NF-κB-mediated gene transcription. The aim of this study is to examine whether NF-κB is involved in the pathogenesis of parathyroid hyperplasia., Methods: 35 PGs was obtained from 10 maintenance hemodialysis patients who underwent parathyroidectomy surgery. 5/6-nephrectomized rats fed with a high-phosphate diet were divided into four groups: (1) Nx + vehicle group, treated with vehicle; (2) Nx + PDTC prevention group, treated with NF-κB inhibitor PDTC for 2 months; (3) Nx + PDTC therapy group, treated with PDTC for 1 month; (4) Nx + calcitriol group, treated with activated vitamin D calcitriol for 1 month. Ten sham-operated rats fed with normal-phosphate diet were used as a control group. Serum calcium, phosphorus, creatinine, Blood urea nitrogen (BUN), intact PTH and PG size in rats were measured. Proliferating cell nuclear antigen (PCNA), VDR, NF-κB of PGs were examined using immunohistochemistry and western blot., Results: The activation of NF-κB pathway in the nodular hyperplasia gland was significantly increased compared with the diffuse hyperplasia gland found in hemodialysis patients. Markedly higher serum creatinine, BUN, phosphorus levels, serum iPTH levels and larger PGs were found in Nx rats fed with a high-phosphate diet compared to sham-operated rats. Also, PCNA levels and activation of NF-κB pathway in PGs were higher compared with the sham group, meanwhile the VDR levels decreased. Contrary, treating rats with PDTC and calcitriol notably reduced serum iPTH, expression of PCNA and activation of NF-κB pathway, and decreased the enlargement of PGs in those animals., Conclusions: NF-κB plays an important role in PG hyperplasia progression. VDR deficiency may be involved in the parathyroid gland hyperplasia through the activation of NF-κB pathway.

Background: Evocalcet has been developed as a new calcimimetic agent for hemodialysis (HD) patients with secondary hyperparathyroidism (HDSHPT), eliciting fewer gastrointestinal symptoms and drug interactions. We evaluated the efficacy, safety, and optimal starting dose of evocalcet in HDSHPT., Methods: In this 3-week, Phase 2b, randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-finding study, Japanese HDSHPT with intact parathyroid hormone (iPTH) ≥240 pg/mL and serum calcium level corrected for albumin ≥8.4 mg/dL were randomized to evocalcet 0.5, 1, 2 mg/day administered orally or placebo under double-blind conditions, and cinacalcet 25 mg/day (open-label conditions)., Results: In total, 152 HDSHPT were randomized. The mean ± standard deviation (median, interquartile range) of percent changes in iPTH from baseline to end of treatment were -8.40±25.43% (-12.16, 39.60), -10.56±22.86% (-14.24, 27.85), and -20.16±34.23% (-23.83, 39.05) in the evocalcet 0.5, 1, and 2 mg/day groups and 5.44±25.85% (3.52, 35.39) and -25.86±27.76% (-29.79, 34.15) in the placebo and cinacalcet groups, respectively. The dose-response profile for each evocalcet group vs placebo showed statistically significant differences for all contrast patterns. Whole PTH, corrected calcium, ionized calcium, phosphorus, and intact fibroblast growth factor 23 decreased after treatment initiation in the evocalcet and cinacalcet groups. Adverse events were observed in 30%-50% of patients (all groups). Incidence of adverse events was similar among all groups except for decreased calcium, which occurred more frequently in the evocalcet 2 mg and cinacalcet groups., Conclusions: The dose response and safety of all administered doses of evocalcet were confirmed, as well as the efficacy of evocalcet ≥1 mg in a strictly Japanese sample of HDSHPT. Therefore, evocalcet 1 mg was considered appropriate as an initial dose for HDSHPT., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr Akizawa has received consulting fees from KHK Co., Ltd., Astellas Pharma Inc., Bayer Yakuhin, Ltd., Fuso Pharmaceutical Industries, Ltd., Japan Tobacco Inc., Ono Pharmaceutical Co., Ltd. and NIPRO Industry, and lecture fees from KHK Co., Ltd., Chugai Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Kissei Pharmaceutical Co., Ltd., Torii Pharmaceutical Co., Ltd. and Ono Pharmaceutical Co., Ltd. Dr Fukagawa has received consulting fees from KHK Co., Ltd. and Ono Pharmaceutical Co., Ltd., and lecture fees from KHK Co., Ltd., Bayer Yakuhin, Ltd., Torii Pharmaceutical Co., Ltd. and Ono Pharmaceutical Co., Ltd., and grants from KHK Co., Ltd. and Bayer Yakuhin, Ltd. Shimazaki is employed by Kyowa Hakko Kirin Co., Ltd. The specific roles of these authors are articulated in the ‘author contributions’ section.” This does not alter our adherence to PLOS ONE policies on sharing data and materials. The evocalcet study group has no conflicts of interest to declare.

Increased levels of parathyroid hormone (PTH) may have adverse effects on bone health. In a cross-sectional design, we investigated this hypothesis among 102 postmenopausal vitamin D insufficient women. Elevated PTH was associated with altered bone geometry, decreased bone mineral density in the spine, and increased bone turnover., Introduction: In vitamin D insufficiency, elevated parathyroid hormone (PTH) levels may contribute to adverse effect on bone. We assessed effects of PTH responses to vitamin D insufficiency on bone metabolism, density, and geometry., Methods: Using a cross-sectional design, we investigated 102 healthy postmenopausal women with low 25-hydroxy-vitamin D (< 50 nmol/L) levels, who had either secondary hyperparathyroidism with elevated PTH levels (> 6.9 pmol/L, N = 51) or normal PTH levels (N = 51). Bone mineral density (BMD) and bone geometry were assessed by Dual-Energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT) and high-resolution peripheral QCT (HRpQCT) scans. Bone metabolism was assessed by biochemistry including bone turnover markers., Results: Levels of 25(OH)D were 38 (IQR 31-45) nmol/L with no differences between groups. PTH levels were 8.5 (IQR 7.5-9.5) in women with SHPT and 5.2 (4.4-6.6) pmol/L in women with normal PTH (p < 0.001). BMI and eGFR did not differ between groups. SHPT was associated with lower total- and trabecular bone area, lower cortical perimeter, and increased cortical area in tibia and radius. SHPT was associated with a lower weight-adjusted BMD at the lumbar spine (p < 0.05). High compared to normal PTH levels were associated with significantly lower plasma levels of 1,25(OH) 2 D, phosphate, but higher levels of osteocalcin and borderline higher levels of CTx. PTH correlated to osteocalcin and CTx., Conclusions: High PTH levels are associated with altered bone geometry, increased bone turnover, and reduced BMD at the spine. Whether an increased cortical thickness with a lower trabecular volume is an effect of PTH or not needs further elucidations.

Canonical Wnt (Wingless/Integrated) signaling is crucial in bone development and the Wnt ligand can promote osteoblast differentiation from mesenchymal progenitor cells. Calcitriol, an active vitamin D3, is used clinically for treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients. The bone effects of calcitriol in SHPT remains uncertain. We hypothesized that calcitriol improves bone mass by suppressing osteoclast activity, and simultaneously promoting Wnt ligand secretion. We designed a cross-sectional study in maintenance hemodialysis patients to explore the effects of calcitriol on different bone turnover markers and specifically emphasized the Wnt 10b levels. Then, we explored the source of Wnt 10b secretion by using osteoclasts and osteoblasts treated with calcitriol in cell culture studies. Finally, we explored the effects of calcitriol on bone microarchitectures in CKD mice, using the 5/6 nephrectomy CKD animal model with analysis using micro-computed tomography. Calcitriol promoted the growth of both trabecular and cortical bones in the CKD mice. Wnt 10b and Procollagen 1 N -terminal Propeptide (P1NP) significantly increased, but Tartrate-resistant acid phosphatase 5b (Trap 5b) significantly decreased in the calcitriol-treated maintenance hemodialysis patients. Calcitriol enhanced Wnt 10b secretion from osteoclasts in a dose-dependent manner. Treatment of SHPT with calcitriol improved the bone anabolism by inhibiting osteoclasts and promoting osteoblasts that might be achieved by increasing the Wnt 10b level.

Chronic kidney disease mineral bone disorder (CKD-MBD) is common in end-stage renal disease and is associated with an increased risk of cardiovascular morbidity and mortality. Mainstays of treatment include decreasing serum phosphorus level toward the normal range with dietary interventions and phosphate binders and treating increased parathyroid hormone levels with activated vitamin D and/or calcimimetics. There is significant variation in serum levels of mineral metabolism markers, intestinal absorption of phosphorus, and therapeutic response among individual patients and subgroups of patients with end-stage renal disease. This variation may be partly explained by polymorphisms in genes associated with calcium and phosphorus homeostasis such as the calcium-sensing receptor gene, the vitamin D-binding receptor gene, and genes associated with vascular calcification. In this review, we discuss how personalized medicine may be used for the management of CKD-MBD and how it ultimately may lead to improved clinical outcomes. Although genetic variants may seem attractive targets to tailor CKD-MBD therapy, complete understanding of how these polymorphisms function and their clinical utility and applicability to personalized medicine need to be determined., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Context: Hyperparathyroidism is associated with hypercalcemia and the excess of parathyroid hormone secretion; however, the alterations in molecular pattern of functional genes during parathyroid tumorigenesis have not been unraveled. We aimed at establishing transcriptional patterns of normal and pathological parathyroid glands (PGs) in sporadic primary (HPT1) and secondary hyperparathyroidism (HPT2)., Objective: To evaluate dynamic alterations in molecular patterns as a function of the type of PG pathology, a comparative transcript analysis was conducted in subgroups of healthy samples, sporadic HPT1 adenoma and hyperplasia, and HPT2., Design: Normal, adenomatous, HPT1, and HPT2 hyperplastic PG formalin-fixed paraffin-embedded samples were subjected to NanoString analysis. In silico microRNA (miRNA) analyses and messenger RNA-miRNA network in PG pathologies were conducted. Individual messenger RNA and miRNA levels were assessed in snap-frozen PG samples., Results: The expression levels of c-MET, MYC, TIMP1, and clock genes NFIL3 and PER1 were significantly altered in HPT1 adenoma compared with normal PG tissue when assessed by NanoString and quantitative reverse transcription polymerase chain reaction. RET was affected in HPT1 hyperplasia, whereas CaSR and VDR transcripts were downregulated in HPT2 hyperplastic PG tissue. CDH1, c-MET, MYC, and CaSR were altered in adenoma compared with hyperplasia. Correlation analyses suggest that c-MET, MYC, and NFIL3 exhibit collective expression level changes associated with HPT1 adenoma development. miRNAs, predicted in silico to target these genes, did not exhibit a clear tendency upon experimental validation., Conclusions: The presented gene expression analysis provides a differential molecular characterization of PG adenoma and hyperplasia pathologies, advancing our understanding of their etiology.

Etelcalcetide, a d-amino acid peptide, is an intravenous calcimimetic approved for the treatment of secondary hyperparathyroidism. Etelcalcetide binds the calcium-sensing receptor and increases its sensitivity to extracellular calcium, thereby decreasing secretion of parathyroid hormone (PTH) by chief cells. Etelcalcetide and its low-molecular-weight transformation products are rapidly cleared by renal excretion in healthy subjects, but clearance is substantially reduced and dependent on hemodialysis in end-stage renal disease. The effective half-life is 3-5 days in patients undergoing hemodialysis 3 times a week. A clinical study using a single microtracer intravenous dose of [ 14 C]etelcalcetide indicated that 60% of the administered dose was eliminated in dialysate. Etelcalcetide undergoes reversible disulfide exchange with serum albumin to form a serum albumin peptide conjugate that is too large (67 kDa) to be dialyzed, until a subsequent exchange forms etelcalcetide or a low-molecular-weight transformation product. This exchange from albumin is apparent after hemodialysis, when it partially restores etelcalcetide concentrations in plasma. Etelcalcetide has no known risks for drug-drug interactions. In phase 3 studies, 74%-75% of hemodialysis patients with secondary hyperparathyroidism who received etelcalcetide achieved a >30% PTH reduction from baseline versus 8%-10% of patients who received placebo. The pharmacokinetics and pharmacodynamics of etelcalcetide in hemodialysis patients supports a 5-mg starting dose administered after hemodialysis and uptitration in 2.5- or 5-mg increments every 4 weeks to a maximum dose of 15 mg 3 times a week., (© 2018, The American College of Clinical Pharmacology.)

SHPT is one of the most common complications of CKD-MBD. Recent studies indicate that oxyphil cell proliferation is related to SHPT progression, while not inhibited by current treatments. The aim of this study was to analyze the correlation between oxyphil cell and clinical indicators in SHPT, further explore the protein expression differences of oxyphil cell. Among 33 MHD patients, 84.8% patients have one or more oxyphil dominant glands and the overall oxyphil cells proportion was 39.5 ± 16.3%. Univariate correlation and multivariable linear regression model showed that oral calcitriol dosage and treatment duration were independently correlated to oxyphil cell ratio. Proteomic study showed that mitochondrial protein, protein synthesis, and cell cycle regulation were significantly altered in oxyphil cell nodules. DBP was downregulated in oxyphil nodules on protein level, which may contribute to calcitriol resistance by reducing vitamin D transport. Through KEGG and PPI network analysis, Wnt signaling, TGF-β, ubiquitin mediated proteolysis and cell cycle pathways were significantly enriched in oxyphil cell nodules. Among which, MIF-CUL1 axis was significantly increased. These results suggest that the limitations of vitamin D in SHPT treatment is closely related to oxyphil cell and may be attributed to the dysregulation of vitamin D transport and ubiquitin regulation of oxyphil cell., Significance: Secondary hyperparathyroidism in end stage renal patients is one of the major challenges nephrology field faces. Emerging data indicate that oxyphil cell may participate in the pathophysiology of secondary hyperparathyroidism, while both calcimimetics and vitamin D receptor activators treatments are underperformed in controlling oxyphil cell proliferation. In the present study, we validated that the proliferation of oxyphil cells is associated with calcitriol treatment, and discovered that oxyphil cell nodules were significantly different from chief cells nodules in protein expression of mitochondria, protein synthesis and cell cycle regulation. It is noteworthy that DBP was downregulated in oxyphil nodules on protein level and may therefore participate in the resistance of calcitriol therapy by reducing the vitamin D transport capacity. Wnt signaling, TGF-β, ubiquitin mediated proteolysis and cell cycle pathways were significantly enriched in oxyphil cell nodules, among which, MIF-CUL1 axis may play an important role in the regulation of oxyphil proliferation and calcitriol resistance through ubiquitin mediated proteolysis. These results suggest that calcitriol treatment has limitations in oxyphil cell predominant SHPT, which may be attributed to the dysregulation of vitamin D transport and ubiquitin regulation of oxyphil cell, and the influence of microenvironment in uremia status may be the underlying reason., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Changes in mineral metabolism and bone structure develop early in the course of chronic kidney disease and at end-stage are associated with increased risk of fragility fractures. The disruption of phosphorus homeostasis leads to secondary hyperparathyroidism, a common complication of chronic kidney disease. However, the molecular pathways by which high phosphorus influences bone metabolism in the early stages of the disease are not completely understood. We investigated the effects of a high phosphorus diet on bone and mineral metabolism using a 5/6 nephrectomy model of chronic kidney disease., Methods: Four-week old rats were randomly assigned into groups: 1) Control with standard diet, 2) Nephrectomy with standard rodent diet, and 3) Nephrectomy with high phosphorus diet. Rats underwent in vivo imaging at baseline, day 14, and day 28, followed by ex vivo imaging., Results: Cortical bone density at the femoral mid-diaphysis was reduced in nephrectomy-control and nephrectomy-high phosphorus compared to control rats. In contrast, trabecular bone mass was reduced at both the lumbar vertebrae and the femoral secondary spongiosa in nephrectomy-high phosphorus but not in nephrectomy-control. Reduced trabecular bone volume adjusted for tissue volume was caused by changes in trabecular number and separation at day 35. Histomorphometry revealed increased bone resorption in tibial secondary spongiosa in nephrectomy-control. High phosphorus diet-induced changes in bone microstructure were accompanied by increased serum parathyroid hormone and fibroblast growth factor 23 levels., Conclusion: Our study demonstrates that changes in mineral metabolism and hormonal dysfunction contribute to trabecular and cortical bone changes in this model of early chronic kidney disease.

Background/aims: Oxidative stress is one of the leading factors contributing to increased mortality in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism (sHPT). Cinacalcet is now commonly used in the treatment of sHPT in patients with CKD. The aim of this study was to assess the influence of treatment with cinacalcet on the oxidative stress markers in patients on hemodialysis with sHPT., Methods: In 58 hemodialysed patients with sHPT (parathyroid hormone [PTH] > 300 pg/mL) plasma Advanced Oxidation Protein Products (AOPP), serum total antioxidant capacity - ImAnOx (TAS/TAC), serum PTH, calcium and phosphate concentrations were assessed before the first dose of cinacalcet and after 6 months of treatment., Results: Serum PTH concentration decreased significantly from 895 (748-1,070) to 384 (289-510) pg/mL after 6 months of treatment; p < 0.0001. Mean serum concentrations of -calcium and phosphate remained stable. Plasma AOPP concentration decreased significantly from 152 (126-185) to 49 -(43-57) µmol/L after 6 months of treatment; p < 0.0001. ImAnOx significantly increased from 260 (251-270) to 272 (264-280) µmol/L; p = 0.04. After 6 months of treatment, a significant, positive correlation was found between ImAnOx and the daily dose of cinacalcet (r = 0.30; p = 0.02). Also, the change of serum ImAnOx during treatment with cinacalcet significantly correlated with the daily dose of cinacalcet r = 0.35; p = 0.01. No significant correlations were found between plasma AOPP concentration or ImAnOx and PTH, or their changes in time., Conclusions: (1) Six-month treatment based on cinacalcet seems to reduce oxidative stress markers in maintenance hemodialysis patients with sHPT. (2) This benefit may be related rather to the direct action of cinacalcet than to the serum PTH concentration decrease., (© 2018 S. Karger AG, Basel.)

The interplay between vitamin D and parathyroid hormone (PTH) represents one of the most important metabolic mechanisms of regulation of the calcium/phosphorus homeostasis. Secondary hyperparathyroidism is therefore a major complication that arises as a result of reduced vitamin D levels, both as primary 25-hydroxy-vitamin D (25[OH]D) and/or 1,25-dihydroxyvitamin D (1,25[OH]2D) reduction. Different metabolic pathways are involved, as well as target organs and tissues, with several clinical complications. The skeleton is primarily involved, but many other extra-skeletal organs expressing the vitamin D and/or PTH receptors may theoretically be affected by vitamin D inadequacy and secondary hyperparathyroidism. Mechanisms associated with low vitamin D (mostly, but not exclusively 1,25[OH]2D deficiency) and high serum PTH also intensify chronic kidney disease (CKD), with further consequences on the mineral metabolism system and development of skeletal and cardiovascular disease. Therapeutic intervention is primarily aimed at enhancing serum 25(OH)D levels and reducing secondary hyperparathyroidism, by employing different strategies and endpoints according to the clinical contest. This chapter reviews the current knowledge on the metabolic pathways involved in the vitamin D/PTH axis regulation in different clinical settings and gives an update on the recommended treatment strategies., (© 2018 S. Karger AG, Basel.)