Does Vitamin D Receptor and Calcium Receptor Activation Therapy Play a Role in the Histopathologic Alterations of Parathyroid Glands in Refractory Uremic Hyperparathyroidism?

Lomonte, Carlo; Vernaglione, Luigi; Chimienti, Domenico; Bruno, Andrea; Cocola, Savino; Teutonico, Annalisa; Cazzato, Francesco; Basile, Carlo

doi:10.2215/cjn.04150907

Cited by 40 publications

(42 citation statements)

References 19 publications

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“…Nodular hyperplasia was defined by well circumscribed, encapsulated nodules with virtually fat cell-free accumulation. 25 We found a direct association between parathyroid AP2 and TGF-␣ levels. Indeed, highest AP2 levels occurred in nodular areas coinciding with their higher TGF-␣ expression; however, AP2 subcellular localization rendered unexpected results.…”

Section: B) and Immunofluorescence Studies (mentioning

confidence: 53%

Activator Protein 2α Mediates Parathyroid TGF-α Self-Induction in Secondary Hyperparathyroidism

Arcidiacono

Cozzolino

Spiegel

et al. 2008

Journal of the American Society of Nephrology

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In secondary hyperparathyroidism, enhanced expression of TGF-␣ in the parathyroid leads to its own upregulation, generating a feed-forward loop for TGF-␣ activation of its receptor, EGFR receptor (EGFR), which promotes parathyroid hyperplasia. These studies examined the role of activator protein 2␣ (AP2), an inducer of TGF-␣ gene transcription, in the upregulation of parathyroid TGF-␣ in secondary hyperparathyroidism. In rat and human secondary hyperparathyroidism, parathyroid AP2 expression strongly correlated with TGF-␣ levels and with the rate of parathyroid growth, as expected. Furthermore, the increases in rat parathyroid content of AP2 and its binding to a consensus AP2 DNA sequence preceded the increase in TGF-␣ induced by high dietary phosphate. More significant, in A431 cells, which provide a model of enhanced TGF-␣ and TGF-␣ self-induction, mutating the core AP2 site of the human TGF-␣ promoter markedly impaired promoter activity induced by endogenous or exogenous TGF-␣. Important for therapy, in five-sixths nephrectomized rats fed high-phosphate diets, inhibition of parathyroid TGF-␣ self-induction using erlotinib, a highly specific inhibitor of TGF-␣/EGFR-driven signals, reduced AP2 expression dosage dependently. This suggests that the increases in parathyroid AP2 occur downstream of EGFR activation by TGF-␣ and are required for TGF-␣ self-induction. Indeed, in A431 cells, erlotinib inhibition of TGF-␣ self-induction caused parallel reductions in AP2 expression and nuclear localization, as well as TGF-␣ mRNA and protein levels. In summary, increased AP2 expression and transcriptional activity at the TGF-␣ promoter determine the severity of the hyperplasia driven by parathyroid TGF-␣ self-upregulation in secondary hyperparathyroidism. 19: 191919: -192819: , 200819: . doi: 10.1681 In chronic kidney disease (CKD), elevated serum levels of parathyroid hormone (PTH) cause osteitis fibrosa, a high-turnover bone disease responsible for bone loss and an excess of calcium (Ca) and phosphate (P) ions in the circulation that predispose to vascular calcification, adverse cardiovascular events, and, consequently, increased morbidity and mortality rates in this patient population. [1][2][3] The severity of parathyroid hyperplasia determines not only the elevations in serum PTH 4 -6 but also the reductions in parathyroid vitamin D receptor content and calcium-sensing receptor expression that render these patients' disease refractory to therapy. J Am Soc NephrolIn human and experimental kidney disease, hypocalcemia, hyperphosphatemia, and 1,25-dihydroxyvitamin D (calcitriol) deficiency are the main determinants of parathyroid hyperplasia. In contrast, dietary P restriction, high Ca intake, and cal-

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Section: B) and Immunofluorescence Studies (mentioning

confidence: 53%

Activator Protein 2α Mediates Parathyroid TGF-α Self-Induction in Secondary Hyperparathyroidism

Arcidiacono

Cozzolino

Spiegel

et al. 2008

Journal of the American Society of Nephrology

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“…Indeed, data on the effect of cinacalcet on the pathology of human PTG in HP with SHPT are very few (33,34,36). Lomonte et al did not find significant differences in the number, weight, and percentage of NH in the PTG of patients who received calcitriol and cinacalcet with respect to those who received calcitriol only.…”

Section: Discussionmentioning

confidence: 97%

“…Moreover, the hypothetical regression of the volume of PTG (reduction of cell proliferation and/or increase in cell apoptosis) in relation to the degree of glandular hyperplasia and to the type of treatment is still an argument for debate (33,34).…”

Section: Introductionmentioning

confidence: 99%

Histology and immunohistochemistry of the parathyroid glands in renal secondary hyperparathyroidism refractory to vitamin D or cinacalcet therapy

Vulpio

Bossola

Stasio

et al. 2013

European Journal of Endocrinology

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Background: Cinacalcet is a new effective treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients (HP), but the alterations of parathyroid gland (PTG) hyperplasia determined by cinacalcet and vitamin D have not been extensively investigated in humans. Methods: We performed histological analyses of 94 PTGs removed from 25 HP who underwent parathyroidectomy (PTx) because of SHPT refractory to therapy with vitamin D alone (group AZ13 HP and 46 PTGs) or associated with cinacalcet (group BZ12 HP and 48 PTGs). The number, weight, the macroscopic cystic/hemorrhagic changes, and type of hyperplasia of PTG (nodularZNH, diffuseZDH) were assessed. In randomly selected HP of group A (4 HP and 14 PTGs) and group B (4 HP and 15 PTGs), the labeling index of cells positive to Ki-67 and TUNEL and the semiquantitative score of immunohistochemistry staining of vitamin D receptor, calcium-sensing receptor, and vascular endothelial growth factor-a (VEGF-a) were measured in the entire PTGs and in the areas with DH or NH. Results: The number and weight of single and total PTG of each HP were similar in the two groups as well as the number of PTG with macroscopic cystic/hemorrhagic areas. TUNEL, Ki-67, and VEGF-a scores were higher in NH than in DH areas. Conclusion: This observational study of a highly selected population of HP, submitted to PTx because SHPT refractory to therapy, shows that the macroscopic, microscopic, and immunochemistry characteristics of PTG in HP who received or did not receive cinacalcet before PTx did not differ significantly.

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“…Adverse gastrointestinal events also occurred more frequently in patients with enlarged glands. Given that some patients develop resistance to cinacalcet therapy and need to be referred for surgery (37,38), the observed difficulty in managing mineral metabolism and the limited use of cinacalcet because of safety concerns might imply future resistance to cinacalcet in these patients. Studies of much longer duration will be required to examine this possibility.…”

Section: Discussionmentioning

confidence: 99%

Cinacalcet Effectively Reduces Parathyroid Hormone Secretion and Gland Volume Regardless of Pretreatment Gland Size in Patients with Secondary Hyperparathyroidism

Komaba¹,

Nakanishi²,

Fujimori³

et al. 2010

Clinical Journal of the American Society of Nephrology

127

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Background and objectives: Cinacalcet is effective in reducing serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. However, it has not been proven whether parathyroid gland size predicts response to therapy and whether cinacalcet is capable of inducing a reduction in parathyroid volume.Design, setting, participants, & measurements: This 52-week, multicenter, open-label study enrolled hemodialysis patients with moderate to severe secondary hyperparathyroidism (intact PTH >300 pg/ml). Doses of cinacalcet were adjusted between 25 and 100 mg to achieve intact PTH <180 pg/ml. Ultrasonography was performed to measure the parathyroid gland size at baseline, week 26, and week 52. Findings were also compared with those of historical controls.Results: Of the 81 subjects enrolled, 56 had parathyroid glands smaller than 500 mm 3 (group S) and 25 had at least one enlarged gland larger than 500 mm 3 (group L). Treatment with cinacalcet effectively decreased intact PTH by 55% from baseline in group S and by 58% in group L. A slightly greater proportion of patients in group S versus group L achieved an intact PTH <180 pg/ml (46 versus 32%) and a >30% reduction from baseline (88 versus 78%), but this was not statistically significant. Cinacalcet therapy also resulted in a significant reduction in parathyroid gland volume regardless of pretreatment size, which was in sharp contrast to historical controls (n ‫؍‬ 87) where parathyroid gland volume progressively increased with traditional therapy alone.Conclusions: Cinacalcet effectively decreases serum PTH levels and concomitantly reduces parathyroid gland volume, even in patients with marked parathyroid hyperplasia.

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Does Vitamin D Receptor and Calcium Receptor Activation Therapy Play a Role in the Histopathologic Alterations of Parathyroid Glands in Refractory Uremic Hyperparathyroidism?

Cited by 40 publications

References 19 publications

Activator Protein 2α Mediates Parathyroid TGF-α Self-Induction in Secondary Hyperparathyroidism

Activator Protein 2α Mediates Parathyroid TGF-α Self-Induction in Secondary Hyperparathyroidism

Histology and immunohistochemistry of the parathyroid glands in renal secondary hyperparathyroidism refractory to vitamin D or cinacalcet therapy

Cinacalcet Effectively Reduces Parathyroid Hormone Secretion and Gland Volume Regardless of Pretreatment Gland Size in Patients with Secondary Hyperparathyroidism

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