Effects of evocalcet on parathyroid calcium-sensing receptor and vitamin D receptor expression in uremic rats.

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.

High sodium promotes the secretion and synthesis of PTH through PiT-1-IKKß pathway in parathyroid gland in vitro.

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 IKKß phosphorylation, IKBα degradation, and increased p65 phosphorylation followed by nuclear entry, which led to increased PTH transcription. Meanwhile, IKKß 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).

Cambios en el metabolismo óseo y mineral en pacientes con Enfermedad Renal Crónica sometidos a trasplante renal en el Hospital General Plaza de la Salud durante el período comprendido entre enero 2010­agosto 2018 / Changes in bone and mineral metabolism in patients with chronic kidney disease undergoing kidney transplantation at Plaza de la Salud General Hospital during the period between January 2010­August 2018

Introducción: las alteraciones del metabolismo óseo-mineral, son una causa importante de morbilidad en los pacientes con trasplante renal, por lo que el manejo de las complicaciones del paciente trasplantado, a largo plazo, deben de ser seguidas. El estudio intenta demostrar cambios en el metabolismo óseo y mineral en pacientes con enfermedad renal crónica sometidos a trasplante renal en el Hospital General Plaza de la Salud durante el período comprendido entre enero 2010 ­ agosto 2018, Santo Domingo, República Dominicana. Método: estudio observacional, descriptivo, retrospectivo y transversal de 131 trasplantes realizados en el Hospital General Plaza de la Salud, evaluando cambios de calcio (Ca), fósforo (P) y hormona paratiroidea (PTH) antes y tres meses post-trasplante. Resultados: la edad media de los pacientes incluidos fue 43.1 ±13.1 años, 72.51 % pertenecía al sexo masculino, con un tiempo medio en hemodiálisis en meses de 27.0 ± 33.6, 60 % de los trasplantes realizados fueron de donante vivo y un 63 % de los pacientes tenía HTA como comorbilidad. El nivel medio de PTH disminuyó en los primeros 3 meses posteriores al trasplante comparado con el pre-trasplante (779.6 ± 1004.0 vs. 167.9 ± 138.2 pg/ml). El fosfato disminuyó significativamente (4.9 ± 1.6 vs. 3.5 ± 0.8) y el calcio aumentó (9.0 ± 1.2 mg/dl vs. a 9.7± 0.8 mg/dl). Discusión: los cambios generales en los niveles séricos de Ca, P, PTH, BUN y creatinina desde el momento del TR a los 3 meses post TR, fueron todos significativos

Introduction: Alterations of bone-mineral metabolism are an important cause of morbidity in patients with kidney transplantation, so the management of long-term transplant patient complications should be followed. The study tries to demonstrate changes in bone and mineral metabolism in patients with chronic renal disease undergoing kidney transplant in the Hospital General Plaza de la Salud during the period January 2010 to August 2018, Santo Domingo, Dominican Republic. Method: Observational, Descriptive, Retrospective and Cross-sectional Study of 131 transplants performed at Hospital General Plaza de la Salud, evaluating changes of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) before and 3 months post-transplant. Results: The mean age of the patients included was 43.1 ± 13.1 years, 72.51% belonged to the male sex, with a mean time on hemodialysis in months of 27.0 ± 33.6, 60% of the transplants performed were from live donors and 63% from the patients had hypertension as comorbidity. The mean PTH level decreased in the first 3 months after transplantation compared to the pre-transplant (779.6 ± 1004.0 vs 167.9 ± 138.2 pg/ml). Phosphate decreased significantly (4.9 ± 1.6 vs 3.5 ± 0.8) and calcium increased (9.0 ± 1.2 mg / dl vs. 9.7 ± 0.8 mg / dl). Discussion: The general changes in serum levels of Ca, P, PTH, BUN and Creatinine from the time of TR to 3 months post TR were all significant

[Cultivation and characterization of primary human parathyroid cells from patients with severe secondary hyperparathyroidism].

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.

Integrated transcriptomic and proteomic analyses for the characterization of parathyroid oxyphil cells in uremic patients.

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.

An optogenetic approach for regulating human parathyroid hormone secretion.

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.

Interrelationships Between Sclerostin, Secondary Hyperparathyroidism, and Bone Metabolism in Patients on Hemodialysis.

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.

Cultivation and characterization of primary human parathyroid cells from patients with severe secondary hyperparathyroidism / 南方医科大学学报

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.

Association of CYP3A5 polymorphisms and parathyroid hormone with blood level of tacrolimus in patients with end-stage renal disease.

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.

Comparison of different parathyroid autograft project after total parathyroidectomy in patients with secondary hyperparathyroidism.

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.

Local NF-κB Activation Promotes Parathyroid Hormone Synthesis and Secretion in Uremic Patients.

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.

Asymptomatic secondary hyperparathyroidism can mimic sacroiliitis on computed tomography.

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. Chi2 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.

Ectopic and supernumerary parathyroid glands in patients with refractory renal hyperparathyroidism.

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.

Role of Bisphosphonates in The Prevention of Postoperative Hungry Bone Syndrome in Primary Hyperparathyroidism: A Meta-Analysis and Need for Randomized Controlled Trials.

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.

Muscle strength, physical performance, and metabolic changes after subtotal parathyroidectomy for secondary hyperparathyroidism.

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.

The diagnostic value of dual-phase SPECT/CT scintigraphy based on transport kinetics of 99mTc-sestamibi confirmed with histopathological findings in patients with secondary hyperparathyroidism - practical consideration.

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.

PTH hypersecretion triggered by a GABAB1 and Ca2+-sensing receptor heterocomplex in hyperparathyroidism.

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) B1 receptor (GABAB1R) in hyperplastic parathyroid glands (PTGs) of patients with primary and secondary HPT. Targeted ablation of GABAB1R 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/GABAB1R 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/GABAB1R in mediating tonic PTH secretion of PTGs and ascribe aberrant activities of CaSR/GABAB1R heteromer to HPT.

Parathyroid Cell Proliferation in Secondary Hyperparathyroidism of Chronic Kidney Disease.

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.

Treatment of Uremic Tumoral Calcinosis in Maintenance Hemodialysis Patients.

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.