Association of Nodular Hyperplasia With Resistance to Cinacalcet Therapy for Secondary Hyperparathyroidism in Hemodialysis Patients

Hirai, Takayuki; Nakashima, Ayumu; Takasugi, Norihisa; Yorioka, Noriaki

doi:10.1111/j.1744-9987.2010.00843.x

Cited by 23 publications

(20 citation statements)

References 22 publications

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“…Cinacalcet is extremely expensive (∼$1000/month) and does not result in permanent involution of the enlarged parathyroid glands. Parathyroid gland size of >500 mm and nodular hyperplasia of the gland are associated with resistance to cinacalcet therapy . Despite suppression of PTH level, the effect on bone‐osteoid interface has been debated, both in human and animal studies .…”

Section: Discussionmentioning

confidence: 99%

“…Parathyroid gland size of >500 mm 3 and nodular hyperplasia of the gland are associated with resistance to cinacalcet therapy. 10 Despite suppression of PTH level, the effect on boneosteoid interface has been debated, both in human 11 and animal studies. 12 Both patients were relatively deficient on 25-hydroxy vitamin D, which may contribute to cinacalcet utilization in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

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Symmetrical craniofacial hypertrophy in patients with tertiary hyperparathyroidism and high‐dose cinacalcet exposure

Hamrahian

Pitman

Csongrádi

et al. 2012

Hemodialysis International

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We are reporting on a series of two patients with end-stage renal disease on hemodialysis, presented for surgical parathyroidectomy secondary refractory hyperparathyroidism. Both patients had failed maximized medical managements, including higher-than-usual doses of the calcimimetic cinacalcet (270 and 180 mg/day, respectively). On physical exam, both patients had marked symmetrical craniofacial hypertrophy with coarse distortion of facial features, similar in appearance to past reports of Sagliker syndrome. On X-ray and computed tomographic exam, they had peculiar areas of bone absorption on the skull, imitating the radiologic appearance of multiple myeloma. Bone biopsy of the maxilla, however, did not show the expected brown tumor, but rather described only fibrosis and reactive bone formations. This phenotype developed while being on cinacalcet, progressed despite escalation of therapy, and improved only after parathyroidectomy. Both patients developed massive "hungry bone syndrome" after parathyroidectomy necessitating prolonged i.v. calcium infusion. This pattern of severe facial distortion likely represented an adverse consequence of severe tertiary hyperparathyroidism, along with supraphysiologic dose of cinacalcet administration and 25-hydroxy vitamin D deficiency in sensitive individuals. The genetic base of this observation remained unexplained.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Symmetrical craniofacial hypertrophy in patients with tertiary hyperparathyroidism and high‐dose cinacalcet exposure

Hamrahian

Pitman

Csongrádi

et al. 2012

Hemodialysis International

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“…In these cases, severely enlarged parathyroid glands (>1 cm) were detected on ultrasound before RTx. Some studies have indicated that the existence of nodular hyperplasia is an important predictor of resistance to cinacalcet treatment in hemodialysis patients with advanced HPT (11,12). Nodular hyperplasia, an advanced type of parathyroid hyperplasia, is characterized by monoclonal cell proliferation and low densities of calcium‐sensing receptors and vitamin D receptors (13–15).…”

Section: Discussionmentioning

confidence: 99%

Tertiary Hyperparathyroidism Resistant to Cinacalcet Treatment

Okada¹,

Tominaga²,

Izumi³

et al. 2011

Ther Apher Dial

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Cinacalcet hydrochloride (cinacalcet) has been reported to be efficacious for patients with tertiary hyperparathyroidism (THPT). We experienced five patients with THPT requiring parathyroidectomy (PTx) because of resistance to cinacalcet treatment and investigated their clinical characteristics and clinical course. The maximum diameter of the parathyroid gland estimated by ultrasonography before renal transplantation was evaluated. Serum total calcium, phosphorus, intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), and creatinine (Cr) levels were investigated every three months after the administration of cinacalcet and at PTx. After surgery, the Cr levels were followed. In all five patients, at least one parathyroid gland had a largest diameter of more than 1 cm, and the mean diameter was 18.7 mm (range 14.9-24.1 mm). Intact PTH and ALP levels gradually increased after the initiation of cinacalcet and the Cr levels transiently increased after PTx. These findings suggest that the existence of a severely enlarged nodular hyperplastic gland is a main factor involved in resistance to cinacalcet.

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“…Interestingly, Cozzolino et al. have reported that such a RTK‐specific inhibitor seems to be a new therapeutic option for SHPT based on data from an animal model (23), partly because advanced nodular hyperplastic parathyroid cells are resistant to cinacalcet therapy (24).…”

Section: Discussionmentioning

confidence: 99%

Role of Multifunctional Cell Cycle Modulators in Advanced Secondary Hyperparathyroidism

et al. 2011

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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.

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Association of Nodular Hyperplasia With Resistance to Cinacalcet Therapy for Secondary Hyperparathyroidism in Hemodialysis Patients

Cited by 23 publications

References 22 publications

Symmetrical craniofacial hypertrophy in patients with tertiary hyperparathyroidism and high‐dose cinacalcet exposure

Symmetrical craniofacial hypertrophy in patients with tertiary hyperparathyroidism and high‐dose cinacalcet exposure

Tertiary Hyperparathyroidism Resistant to Cinacalcet Treatment

Role of Multifunctional Cell Cycle Modulators in Advanced Secondary Hyperparathyroidism

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