NDT Advance Access originally published online on October 6, 2007
Nephrology Dialysis Transplantation 2008 23(1):408-409; doi:10.1093/ndt/gfm645
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Reply
Sir,Fukagawa et al. pointed out that we did not address the potential effect of calcimimetics on parathyroid gland hyperplasia of the nodular type, i.e., clonal parathyroid growth, in our review on calcimimetics in experimental animals. We agree with Fukagawa et al. that it has so far proved impossible to replicate nodular parathyroid hyperplasia in response to chronic renal failure (CRF) in animal models. However, it is also noteworthy that currently, there is no satisfactory surrogate marker allowing for the differentiation of diffuse parathyroid hyperplasia of the polyclonal type from nodular hyperplasia of the monoclonal or multiclonal type in patients with chronic kidney disease. Although, parathyroid gland volume in excess of 0.5 mm3, as evaluated by ultrasonography, appears to be a useful indicator of autonomous parathyroid cell proliferation, it does not allow any precise distinction. The diagnosis requires molecular genetic analysis of parathyroid tissue.
There is, however, experimental and clinical evidence pointing to the possibility that calcimimetics are able to induce regression of even severe parathyroid hyperplasia. Calcimimetics have been shown to reduce the proliferation of parathyroid glands in uraemic animals [1,2]. In addition, the ability of the calcimimetics to up-regulate the expression of the calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) in parathyroid glands of rats with CRF [3,4] can cause decreased synthesis and secretion of parathyroid hormone (PTH), thereby causing decreased prohyperplastic pressure. Furthermore, cinacalcet has been shown to be efficacious in reducing serum PTH and calcium in dialysis patients with severe parathyroid overfunction [5] (i.e. patients who presumably have nodular parathyroid hyperplasia), in non-uraemic patients with primary hyperparathyroidism [6] and in kidney graft recipients with persistent, autonomic, hyperparathyroidism and hypercalcaemia [7,8]. These data suggest that calcimimetics can be efficacious despite persistent down-regulation of CaSR and VDR in parathyroid glands with nodular hyperplasia [9].
Moreover, clinical evidence suggests that the use of calcimimetics may decrease the rate of parathyroidectomy in dialysis patients [10] and that they may be able to decrease serum PTH, calcium, phosphorus and calcium–phosphorus product in subjects with relapsed secondary HPT and nodular parathyroid hyperplasia (n = 4/6 subjects) or carcinoma (n = 2/6) after parathyroidectomy [11].
Together, these data demonstrate the ability of calcimimetics to improve control of secondary HPT under a variety of conditions potentially associated with advanced parathyroid hyperplasia. While these studies are not definitive, they do suggest that calcimimetics may be effective in the treatment of nodular hyperplasia and that randomized clinical trials would be appropriate.
Conflict of interest statement. None declared.
1Inserm Unit 845 and Division of
Nephrology, Necker Hospital,
Paris, France
2Amgen Inc. Department of Metabolic
Disorders, Thousand Oaks, CA, USA
3Research Unit, Nephrology Service
Hospital Universitario Reina Sofia, Cordoba, Spain
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- Wada M, Furuya Y, Sakiyama J, et al. The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor. J Clin Invest (1997) 100:2977–2983.[Web of Science][Medline]
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[Abstract/Free Full Text]
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