Advanced Secondary Hyperparathyroidism Research Articles

Impact of Parathyroidectomy Versus Oral Cinacalcet on Bone Mineral Density in Patients on Peritoneal Dialysis With Advanced Secondary Hyperparathyroidism: The PROCEED Pilot Randomized Trial

Parathyroidectomy and calcimimetics have been used to reduce fracture risk in patients with kidney failure and advanced secondary hyperparathyroidism (SHPT), but direct comparisons of these treatment approaches have not been implemented. This pilot study compared their effects on bone mineral density (BMD) in this patient population. A prospective pilot open-label randomized trial. 65 patients receiving maintenance peritoneal dialysis with advanced SHPT recruited from 2 university-affiliated hospitals in Hong Kong. Total parathyroidectomy with forearm autografting versus oral cinacalcet treatment for 12 months. Prespecified secondary end points including changes in BMD z and T scores of femoral neck, lumbar spine, and distal radius 12 months after treatment initiation and also categorized as osteopenia or osteoporosis according to the World Health Organization. Both total parathyroidectomy and cinacalcet significantly improved BMD of the lumbar spine and femoral neck over 12 months, but the total parathyroidectomy group had a greater increase than the cinacalcet-treated group (P<0.001). The proportion of study participants classified as having osteopenia/osteoporosis by femoral neck T-score fell from 78.2% to 51.7% in the total parathyroidectomy group (P<0.001) and from 65.7% to 52.0% in cinacalcet-treated group after 12 months (P=0.7). The proportion of participants with a T-score at the lumbar spine classified as osteopenia/osteoporosis fell from 53.1% to 31.0% in the total parathyroidectomy group (P=0.01) and from 59.4% to 53.8% with cinacalcet (P=0.3). No significant change was observed in BMD T or z score of the distal radius over 12 months with either intervention. Bone histology was not assessed, and the study duration was 12 months. A large proportion of peritoneal dialysis patients with advanced SHPT had low bone densities and osteopenia/osteoporosis. Total parathyroidectomy increased the BMD of the lumbar spine and femoral neck and reduced osteopenia/osteoporosis more than oral cinacalcet. Grants from academic (The University of Hong Kong Research) and not-for-profit (Hong Kong Society of Nephrology) entities. Registered at Clinicaltrials.gov with study number NCT01447368. It is not known whether oral cinacalcet and surgical parathyroidectomy differ in their effects on bone parameters in patients with advanced secondary hyperparathyroidism (SHPT) receiving peritoneal dialysis. This pilot randomized trial evaluated the effect of medical versus surgical therapy on bone mineral densities (BMD) as prespecified secondary study end points. The findings showed that a large proportion of peritoneal dialysis patients with advanced SHPT had low bone densities and osteopenia/osteoporosis. Parathyroidectomy increased the BMD of the lumbar spine and femoral neck more than cinacalcet over 12 months. Parathyroidectomy reduced the proportion of patients with osteopenia/osteoporosis at the lumbar spine and femoral neck more than cinacalcet after 12 months. Neither intervention led to an increase in the BMD of the distal radius over 12 months.

Parathyroidectomy versus oral cinacalcet on cardiovascular parameters in peritoneal dialysis patients with advanced secondary hyperparathyroidism (PROCEED): A randomized trial.

This trial aimed to evaluate oral cinacalcet versus total parathyroidectomy with forearm autografting (PTx) on cardiovascular surrogate outcomes and health-related quality of life (HRQOL) measures in dialysis patients with advanced SHPT. In this pilot prospective randomized trial conducted in two university-affiliated hospitals, 65 adult peritoneal dialysis patients with advanced SHPT were randomized to receive either oral cinacalcet or PTx. Primary endpoints were changes in left ventricular (LV) mass index by cardiac magnetic resonance imaging and coronary artery calcium scores (CACS) over 12 months. Secondary endpoints included changes in heart valves calcium scores, aortic stiffness, biochemical parameters of chronic kidney disease-mineral bone disease (CKD-MBD) and HRQOL measures over 12 months. Changes in LV mass index, CACS, heart valves calcium score, aortic pulse wave velocity and HRQOL did not differ between-groups or within-groups, despite significant reductions in plasma calcium, phosphorus and intact parathyroid hormone in both groups. Cinacalcet-treated patients experienced more cardiovascular-related hospitalizations than those who underwent PTx (P=0.008) but the difference became insignificant after adjusting for baseline difference in heart failure (P=0.43). With the same monitoring frequency, cinacalcet-treated patients had fewer hospitalizations due to hypercalcemia (1.8%) than patients who underwent PTx (16.7%) (P=0.005). No significant changes were observed in HRQOL measures in either group. Both cinacalcet and PTx effectively improved various biochemical abnormalities of CKD-MBD and stabilized but did not reduce LV mass, coronary artery and heart valves calcification, arterial stiffness or improve patient-centered HRQOL measures in PD patients with advanced SHPT. Cinacalcet may be used in place of PTx for treating advanced SHPT. Long-term and powered studies are required to evaluate PTx versus cinacalcet on hard cardiovascular outcomes in dialysis patients.

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.

A randomised controlled trial to examine the effects of cinacalcet on bone and cardiovascular parameters in haemodialysis patients with advanced secondary hyperparathyroidism

BackgroundSecondary hyperparathyroidism may lead to increased cardiovascular risk. The use of cinacalcet may improve bone and cardiovascular health with improved parathormone (PTH) and phosphate control.MethodsThis is an open-label prospective randomised controlled trial to compare progression of cardiovascular and chronic kidney disease mineral and bone disorder (CKD-MBD) parameters. Patients were randomised to receive cinacalcet alongside standard therapy or standard therapy alone. Thirty-six haemodialysis patients who had > 90 days on dialysis, iPTH > 300 pg/mL, calcium > 2.1 mmol/L and age 18–75 years were included. Following randomization, all 36 patients underwent an intensive 12-week period of bone disease management aiming for iPTH 150-300 pg/mL. The primary outcome was change in vascular calcification using CT agatston score. Secondary outcomes included pulse wave velocity (PWV), left ventricular mass index (LVMI), carotid intima-media thickness (CIMT), augmentation index (Aix) and bone measurements. The above measurements were obtained at baseline and 12 months.ResultsThere was no evidence of a group difference in the progression of calcification (median change (IQR) cinacalcet: 488 (0 to1539); standard therapy: 563 (50 to 1214)). In a post hoc analysis combining groups there was a mean (SD) phosphate reduction of 0.3 mmol/L (0.7) and median (IQR) iPTH reduction of 380 pg/mL (− 754, 120). Regression of LVMI and CIMT was seen (P = 0.03 and P = 0.001) and was significantly associated with change of phosphate on multi-factorial analyses.ConclusionsWith a policy of intense CKD-MBD parameter control, no significant benefit in bone and cardiovascular markers was seen with the addition of cinacalcet to standard therapy over one year. Tight control of hyperphosphataemia and secondary hyperparathyroidism may lead to a reduction in LVMI and CIMT but this needs further investigation. Although the sample size was small, meticulous trial supervision resulted in very few protocol deviations with therapy.

Is There a Gender Difference in Clinical Presentation of Renal Hyperparathyroidism and Outcome after Parathyroidectomy?

Introduction: Gender has been proven to influence the pathophysiology and treatment of numerous diseases, including kidney diseases and hormonal dysfunction like hyperparathyroidism. Thus, higher parathormone levels have been demonstrated in women with end-stage kidney disease, when compared to men. Objectives: We questioned whether female gender is associated with an increased risk for parathyroid nodular hyperplasia and necessary parathyroidectomy in dialysis patients and assessed demographics as well as outcome data for women and men undergoing parathyroidectomy for renal hyperparathyroidism. Patients and Methods: One hundred and thirty patients (men = 75, female = 55) with end-stage renal disease on chronic dialysis and advanced secondary hyperparathyroidism who underwent parathyroidectomy between 2008 and 2014 at our center were analyzed retrospectively. Perioperative characteristics and short-term outcome were evaluated with respect to biological gender. Results: No differences could be demonstrated for patient demography, comorbidities and the perioperative course between males and females. Only preoperative calcium levels were lower in female than in male patients (2.3 ± 0.19 vs. 2.3 ± 0.26, p = 0.04). There were more women, however, with cerebrovascular complications during follow-up (p = 0.04). There was no postoperative mortality, and all complications and comorbidities with exception of cerebrovascular diseases were equally distributed between female and male patients. Conclusion: Overall, we could not demonstrate many significant differences between male and female patients with end-stage renal diseases, chronic dialysis and operated secondary hyperparathyroidism. Only preoperative electrolyte levels were higher in male than in female patients, and cerebrovascular complications developed more often in females than in males during long-term follow-up.

Prostaglandin E2 receptor EP2 mediates the effect of cyclooxygenase 2 on secondary parathyroid hyperplasia in end-stage renal disease

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. 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. 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. 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.

Two Years of Cinacalcet Hydrochloride Treatment Decreased Parathyroid Gland Volume and Serum Parathyroid Hormone Level in Hemodialysis Patients With Advanced Secondary Hyperparathyroidism

The long-term effect of cinacalcet hydrochloride treatment on parathyroid gland (PTG) volume has been scarcely investigated in patients with moderate to advanced secondary hyperparathyroidism (SHPT). The present study was a prospective observational study to determine the effect of cinacalcet treatment on PTG volume and serum biochemical parameters in 60 patients with renal SHPT, already treated with intravenous vitamin D receptor activator (VDRA). Measurement of biochemical parameters and PTG volumes were performed periodically, which were analyzed by stratification into tertiles across the baseline parathyroid hormone (PTH) level or PTG volume. We also determined the factors that can estimate the changes in PTG volume and the achievement of the target PTH range by multivariable analyses. Two years of cinacalcet treatment significantly decreased the serum levels of PTH, calcium, and phosphate, followed by the improvement of achieving the target ranges for these parameters recommended by the Japanese Society for Dialysis Therapy. Cinacalcet decreased the maximal and total PTG volume by about 30%, and also decreased the serum PTH level independent of the baseline serum PTH level and PTG volume. Ten out of 60 patients showed 30% increase in maximal PTG after 2 years. Multivariable analysis showed that patients with nodular PTG at baseline and patients with higher serum calcium and PTH levels at 1 year were likely to exceed the target range of PTH at two years. In conclusion, cinacalcet treatment with intravenous VDRA therapy decreased both PTG volume and serum intact PTH level, irrespective of the pretreatment PTG status and past treatment history.

The induction of C/EBPβ contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease.

In secondary hyperparathyroidism (SHPT), enhanced parathyroid levels of transforming growth factor-α (TGFα) increase EGF receptor (EGFR) activation causing parathyroid hyperplasia, high parathyroid hormone (PTH) and also reductions in vitamin D receptor (VDR) that limit vitamin D suppression of SHPT. Since anti-EGFR therapy is not an option in human SHPT, we evaluated ADAM17 as a therapeutic target to suppress parathyroid hyperplasia because ADAM17 is required to release mature TGFα, the most potent EGFR-activating ligand. Computer analysis of the ADAM17 promoter identified TGFα and C/EBPβ as potential regulators of the ADAM17 gene. Their regulation of ADAM17 expression, TGFα/EGFR-driven growth and parathyroid gland (PTG) enlargement were assessed in promoter-reporter assays in A431 cells and corroborated in rat and human SHPT, using erlotinib as anti-EGFR therapy to suppress TGFα signals, active vitamin D to induce C/EBPβ or the combination. While TGFα induced ADAM17-promoter activity by 2.2-fold exacerbating TGFα/EGFR-driven growth, ectopic C/EBPβ expression completely prevented this vicious synergy. Accordingly, in advanced human SHPT, parathyroid ADAM17 levels correlated directly with TGFα and inversely with C/EBPβ. Furthermore, combined erlotinib + calcitriol treatment suppressed TGFα/EGFR-cell growth and PTG enlargement more potently than erlotinib in part through calcitriol induction of C/EBPβ to inhibit ADAM17-promoter activity, mRNA and protein. Importantly, in rat SHPT, the correction of vitamin D deficiency effectively reversed the resistance to paricalcitol induction of C/EBPβ to suppress ADAM17 expression and PTG enlargement, reducing PTH by 50%. In SHPT, correction of vitamin D and calcitriol deficiency induces parathyroid C/EBPβ to efficaciously attenuate the severe ADAM17/TGFα synergy, which drives PTG enlargement and high PTH.

Oral paricalcitol for the treatment of secondary hyperparathyroidism in hemodialysis patients

Secondary hyperparathyroidism is common amongst dialysis patients and is associated with increased morbidity and mortality. Vitamin D analogues are effective treatments, but the adverse effects of traditional vitamin D preparations, especially hypercalcemia, are often dose-limiting. We studied the efficacy and safety of paricalcitol for the treatment of secondary hyperparathyroidism in hemodialysis patients. We reviewed 13 adult hemodialysis patients treated with oral paricalcitol. The dosage of paricalcitol was adjusted according to the clinical response. Serum parathyroid hormone (PTH) level decreased by 47.3 ± 34.3% at 3 months and 74.7 ± 36.8 % by 3 years. Eight patients (62%) responded and had reduction in PTH levels by at least 30%; seven of them (87.5%) responded within the first 3 months. Responders had a significantly lower baseline PTH level than the nonresponders (64.3 ± 32.2 vs. 138.5 ± 64.0 pmol/L, p = 0.02). None of the patients developed hypercalcemia, but hyperphosphatemia was present in all patients. There is a substantial improvement in PTH levels by paricalcitol treatment in hemodialysis patients with secondary hyperparathyroidism, and paricalcitol is generally well tolerated. Our results suggest that patients with more advanced secondary hyperparathyroidism tend to have a less favorable response. 在血液透析患者間，次發性甲狀旁腺功能亢進是常見的疾病，會明顯增加患者的死亡與患病率。維生素 D 類似物通常是有效的療法，但傳統製劑的臨床應用常受限於不良作用如高鈣血症的出現。本研究以患有次發性甲狀旁腺功能亢進的血液透析患者為對象，調查了 paricalcitol 在這方面的功效與安全性。 本研究回顧了 13 位成年血液透析患者，正在接受口服 paricalcitol 治療，其劑量根據臨床反應作出調整。 經過 3 個月及 3 年後，血清副甲狀腺素 (PTH) 水平分別下降 47.3 ± 34.3% 及 74.7 ± 36.8%。其中，8 人 (62%) 反應良好，PTH 降幅達至少 30%；他們之中有 7 人 (87.5%) 在首 3 個月呈現反應。相比於不反應者，反應者的基線 PTH 明顯較低 (64.3 ± 32.2 vs 138.5 ± 64.0 pmol/L， p = 0.02)。治療期間，無任何人出現高鈣血症，但所有病人均有高磷酸血症的現象。 對於患有次發性甲狀旁腺功能亢進的血液透析患者，paricalcitol 可有效降低 PTH，且耐受性良好。本研究的結果亦顯示，較晚期的次發性甲狀旁腺功能亢進患者，其療效反應可能較為不明顯。

Decreased expression of calcium-sensing receptor and parafibromin in secondary hyperparathyroidism with an abnormal whole PTH/intact PTH ratio.

A 34-year-old female hemodialysis patient with an abnormal whole parathyroid hormone (PTH)/intact PTH ratio (ratio = 1.14) underwent parathyroidectomy for advanced secondary hyperparathyroidism. The abnormal PTH ratio indicated a relative increase in the serum N-terminus PTH, a new molecular form of PTH. The abnormal ratio normalized immediately after the largest parathyroid gland (PTG) was removed, proving the largest PTG as causative. An immunohistochemical analysis revealed extremely decreased expression of the calcium-sensing receptor and parafibromin in the largest PTG in comparison with the other PTGs. This case indicated the possible involvement of decreased calcium-sensing receptor and parafibromin signaling in the development of the abnormal PTH ratio.

Advantages of hybrid SPECT-CT imaging in preoperative localization of parathyroid glands in a patient with secondary hyperparathyroidism. A case report

SummaryBackground:Secondary hyperparathyroidism is a frequent complication of chronic renal failure. Patients resistant to pharmacotherapy are candidates for parathyroidectomy. Invasiveness of surgical treatment can be minimized by precise preoperative localization of parathyroid glands. Imaging modalities routinely used for this purpose are ultrasonography and MIBI-Tc99m scintigraphy.Case Report:Our case report shows advantages of co-registered computer tomography and conventional SPECT imaging (SPECT/CT) in a patient with advanced secondary hyperparathyroidism successfully treated with surgery.Results:Hybrid SPECT/CT parathyroid imaging enables better surgical planning and is superior to conventional scintigraphy.

Kidney and bone update : the 5-year history and future of CKD-MBD. Parathyroidectomy for secondary hyperparathyroidism

Induction of Cinacalcet HCl (cinacalcet) has influenced treatment of secondary hyperparathyroidism (SHPT) in Japan. The number of parathyroidectomy (PTx) for SHPT has remarkably decreased. Fundamentally patients with advanced SHPT refractory to medical treatment including cinacalcet should require PTx. PTx can release SHPT most dramatically. Because in Japan, many hemodialysis patients are expected for long-term survival, we should decide the indication of PTx concerning long-term treatment and economical aspect. We recommend PTx for patients who are expected for long term survival and SHPT is resistant to vitamin D activators, patients with severe symptoms of SHPT, patients with SHPT resistant to cinacalcet, patients with hypercalcemia and/or hyperphosphatemia resistant to medical treatment, and patients who cannot tolerate to side effect of cinacalcet. Some patients with advanced SHPT which is not controlled by surgical treatment should require cinacalcet therapy as rescuing treatment before operation.

Number of enlarged parathyroid glands might be a predictor of cinacalcet response in advanced secondary hyperparathyroidism

Cinacalcet has been shown to be effective in lowering serum intact parathyroid hormone (iPTH) levels in patients with advanced secondary hyperparathyroidism (SHPT). We investigated clinical factors influencing therapeutic response to cinacalcet for SHPT refractory to active vitamin D sterols. A total of 57 hemodialysis patients with SHPT (iPTH >300pg/mL) were enrolled in this 28-week, prospective, observational study. Cinacalcet was started at an initial dose of 25mg/day; the dose of cinacalcet was titrated to achieve the following: 3.5≤phosphate (P)≤6.0mg/dL; 8.4≤adjusted calcium (Ca)≤10.0mg/dL; 60≤iPTH≤180pg/mL). Parathyroid ultrasonographic examination was performed at the start of cinacalcet treatment. Patients were divided into two groups on the basis of iPTH levels after 28weeks: Group A, iPTH ≤180pg/mL; Group B, iPTH >180pg/mL. Serum iPTH and P levels at baseline were significantly higher in Group B than Group A. The number of enlarged parathyroid glands (PTGs) (estimated volume ≥500mm(3) or major axis ≥10mm), which presumably had nodular hyperplastic lesions, and the largest and the total volume of detectable PTGs were significantly greater in Group B compared with Group A. In our multivariate logistic regression analysis, patients with two or more enlarged PTGs had a significant risk of poor response to cinacalcet treatment (odds ratio 5.68, 95% confidence interval 1.19-32.66, P=0.0363). These results indicate that the number of enlarged PTGs could predict therapeutic response of cinacalcet in patients with advanced SHPT.

Diseases of the parathyroid gland in chronic kidney disease

During the past few years, remarkable advances have been made in the understanding and the management of parathyroid diseases in patients with chronic kidney disease (CKD). One of the important insights is the identification of fibroblastic growth factor 23, which has greatly reshaped our understanding of secondary hyperparathyroidism (SHPT). The recent introduction of calcimimetic cinacalcet hydrochloride has led to a major breakthrough in the management of SHPT. Recognition of circulating molecular forms of parathyroid hormone (PTH) is also a major milestone in the accurate assessment of parathyroid function in CKD. Primary hyperparathyroidism should also be considered in patients with CKD, because it can cause various renal manifestations and can also occur as a sporadic disease in these patients. Hypoparathyroidism is occasionally seen in dialysis patients in the setting of diabetes mellitus and malnutrition-inflammation complex syndrome, as well as after parathyroidectomy for advanced SHPT. For patients with adynamic bone disease due to hypoparathyroidism and/or skeletal resistance to PTH, teriparatide, a PTH analog, may have potential for improving bone metabolism and reducing the risk of fracture. In this review, we summarize our current knowledge on diseases of the parathyroid gland in CKD patients, with a particular focus on recent work in the field.

Calcified Vasa Deferentia

A 60-year-old man with advanced diabetic nephropathy and secondary hyperparathyroidism underwent radiographic imaging of the abdomen and pelvis as part of an evaluation for nephrolithiasis.

Role of Multifunctional Cell Cycle Modulators in Advanced Secondary Hyperparathyroidism

Long-term dialysis for patients with end stage renal disease leads to an unavoidable common complication, which is secondary hyperparathyroidism. Two histological patterns (nodular and diffuse hyperplasia) are detected, indicating that continuous uremia-related stimulation promotes parathyroid cell proliferation from diffuse to nodular growth. However, the key molecular mechanism is not fully understood, which narrows the range of therapeutic options for advanced secondary hyperparathyroidism. To address this issue, we utilized surgically resected normal and hyperplastic parathyroid glands to perform immunohistochemical analysis of a multifunctional cell cycle modulator, CCAAT enhancer binding protein (C/EBP)β. In contrast to normal parathyroid tissue and diffuse hyperplasia, the intensity of C/EBPβ staining was homogeneously increased in the parathyroid cells from nodules, along with a higher cyclin D1 labeling index (108.0 ± 19.5, mean ± SEM) and Ki-67 labeling index (31.70 ± 0.49). Normal and diffuse hyperplastic parathyroid glands had far fewer cyclin D1- and Ki-67-positive cells (P < 0.001). Immunofluorescent double staining showed abundant coexpression of Th235 (mitogen-activated protein kinase [MAPK] phosphorylation site) C/EBPβ, along with upregulation of cytoplasmic Ras in nodular hyperplasia. In conclusion, hyperplastic parathyroid cells in nodules have an autonomous proliferation mechanism similar to that of cancer, in which C/EBPβ is upregulated and phosphorylated to interact with the oncogenic Ras/MAPK pathway. C/EBPβ may be a novel target molecule for blocking the growth circuit that underlies parathyroid tumorigenesis in secondary hyperparathyroidism.

Parathyroid Gland Ultrasound Patterns and Biochemical Findings After One‐year Cinacalcet Treatment for Advanced Secondary Hyperparathyroidism

Cinacalcet efficacy is limited in severe secondary hyperparathyroidism (SHPT) and its effect on parathyroid gland (PTG) volume and morphology have not been sufficiently investigated. We evaluated the effect of cinacalcet treatment for one year on the laboratory parameters of calcium-phosphorus metabolism and PTG ultrasound (US) patterns in hemodialysis (HD) patients with severe SHPT and US results indicative of nodular hyperplasia. Thirteen HD patients with severe SHPT (intact parathyroid hormone >700 pg/mL), US/scintigraphic evidence of at least one PTG with a diameter >7 mm, and high surgical risk or refusal of surgery were included. The patients were treated with cinacalcet. The initial dose of 30 mg was increased up to 180 mg once daily. At baseline and after one year of cinacalcet treatment a neck US was performed, providing data on 22 parathyroid glands in eight patients. The mean diameter at baseline and at one year was 12.6 +/- 5.9 and 13.0 +/- 5.3 mm, respectively (P = 0.46). Similarly, the mean volume at baseline and at one year was 513.4 +/- 416.3 and 556.8 +/- 480.8 mm(3), respectively (P = 0.18). The US structural score remained unchanged in 16 parathyroid glands and increased in 6 (P < 0.03), while the vascular score remained unchanged in 16 parathyroid glands and decreased in 6 (P = 0.25). Thus it can be concluded that cinacalcet treatment for one year in HD patients with severe SHPT is not associated with significant changes in parathyroid gland US patterns.

Cinacalcet – Clinical and Laboratory Effectiveness, Concomitant Treatment Patterns and Treatment Cost: Could We Do Better and How?

Background: The cost and effectiveness patterns in the treatment of secondary hyperparathyroidism (SHPT) in dialysis patients in the Czech Republic are unknown. Methods: 52 dialysis patients from 17 centers were followed up in a multicenter prospective study of laboratory and clinical (hospitalization rate, clinical complaints questionnaire) responses to 12-month cinacalcet treatment. Treatment patterns and cost (including phosphate binders, vitamin D, and cinacalcet) were evaluated. Results: The mean s-Ca dropped significantly from 2.36 ± 0.24 to 2.21 ± 0.20 mmol/l, s-P from 2.45 ± 0.54 to 2.01 ± 0.53 mmol/l, Ca×P from 5.79 ± 1.25 to 4.42 ± 1.13 mmol²/l², and iPTH dropped from 919.0 ± 465.6 to 372.1 ± 294.6 pg/ml. The mean cinacalcet dose reached 44.1 ± 23.0 mg/day after 12 months. Itching intensity decreased significantly. No change in hospitalization rate was observed. The direct cost of daily SHPT treatment rose significantly from EUR 8.77 ± 9.59 to 20.62 ± 9.22. Conclusions: Cinacalcet decreased elevated s-Ca, s-P, Ca×P, and iPTH, alleviated itching, and significantly raised the SHPT treatment cost. A minority of patients reached K/DOQI targets, especially due to poor phosphate control caused by insufficient phosphate binder treatment, cinacalcet underdosing, and advanced SHPT.

Gender Differences Among Patients with Secondary Hyperparathyroidism Undergoing Parathyroidectomy

Female gender is associated with an increased risk of parathyroid nodular hyperplasia and parathyroidectomy rate in dialysis patients. The purpose of this study was to assess differences between women and men undergoing parathyroidectomy for secondary hyperparathyroidism. We reviewed 121 consecutive patients with end-stage renal disease and advanced secondary hyperparathyroidism who underwent parathyroidectomy between 2004 and 2007. Preoperative characteristics and short-term outcome of these patients were evaluated. Compared with men (n = 43), women (n = 78) had lower preoperative bone mineral density (both T-scores and Z-scores) as well as lower preoperative hemoglobin levels. The cause of renal failure was also different between the two groups. No differences in preoperative calcium-phosphorus product, alkaline phosphatase, or parathyroid hormone levels were observed. Follow-up analysis showed that biochemical improvement and 1-y recurrence rate was similar between genders. Women with secondary hyperparathyroidism had worse bone mineral metabolism before parathyroidectomy. Additional research regarding target organ susceptibility to hyperparathyroidism in different genders is warranted.

Chronic kidney disease (CKD) and bone. The clinical perspective of parathyroid interventional therapy for advanced secondary hyperparathyroidism in the era of cinacalcet HCl

Advanced secondary hyperparathyroidism (SHPT) due to chronic kidney disease refractory to medical treatment should be indicated for parathyroid interventional therapy (parathyroidectomy [PTX] and percutaneous ethanol injection therapy [PEIT] ect). Japanese Society of Dialysis Therapy (JSDT) guideline recommends performing PTX at relatively early stage of SHPT in order to improve patient's mortality. Cinacalcet HCl should influence the treatment of SHPT in our country. Because PTX can dramatically control SHPT and majority of Japanese dialysis patients have to continue hemodialysis for long-term, PTX should be performed in patients in whom SHPT is refractory to vitamin D therapy, moreover and Cinacalcet HCl and can not tolerate to continue Cinacalcet HCl due to side effects. However surgeons hesitate the operation for patients who belong to high risk group and have the possibility of severe complications, suffer from parathyroid carcinoma or parathyromatosis. Cinacalcet HCl may be indicated for these patients. SHPT can be managed for long-term by PEIT, provided that only one parathyroid gland is enlarged. Indication of PEIT may be limited by Cinacalcet HCl.