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NDT Advance Access published online on November 5, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn587
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


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Nephrol Dial Transplant 2008; doi:10.1093/ndt/gfn579

Correspondence and offprint requests to: E-mail: fukagawa{at}med.kobe-u.ac.jp

Sir,

We would like to thank Dr Terawaki et al. for their interest in our article [1] and for the opportunity to comment on their case report [2]. As brought up by them, the effect of calcimimetics on the size of parathyroid hyperplasia has been an issue of concern, but still remains controversial [3]. In patients with chronic kidney disease, several factors, such as phosphate retention, hypocalcaemia and calcitriol deficiency, stimulate PTH secretion, and then induce hypertrophy and proliferation of parathyroid cells [4]. Theoretically, if such PTH secretion is pharmacologically suppressed for a long term, regression of gland mass could be induced, as previously shown in a study of calcitriol pulse therapy [5]. Such regression of parathyroid hyperplasia usually occurs in small glands with diffuse hyperplasia [6], while regression of nodular hyperplasia can be induced only by direct vitamin D injection therapy [7].

So far, several in vivo studies have shown that calcimimetics inhibit the development and progression of parathyroid hyperplasia [8,9], and also upregulate the expression of calcium-sensing receptor and vitamin D receptor (VDR) that were shown to be reduced in the setting of uraemia [10,11]. However, it is technically difficult to confirm the actual regression of parathyroid hyperplasia in rodent studies, and data on the effect of calcimimetics on the size of parathyroid hyperplasia are limited [12]. An in vitro study has shown that extremely high concentrations of calcimimetics induce apoptosis of parathyroid cells [13], but this study does not reproduce the actual setting of dialysis patients treated with calcimimetics.

In this regard, the case presented by Dr Terawaki et al. is of great interest. They indicated the possibility that calcimimetics may have a potential to regress the established parathyroid hyperplasia. Indeed, we also experienced a few similar cases in whom the size of parathyroid glands was reduced during cinacalcet treatment. In addition, we further experienced a case of severe hyperparathyroidism associated with a markedly enlarged parathyroid gland, which became hypovascularized during cinacalcet treatment (unpublished data); it is possible that such a hypovascularized gland may become smaller after longer cinacalcet treatment.

However, it is still unclear whether such regression of parathyroid hyperplasia can be induced universally in dialysis patients treated with cinacalcet. Furthermore, we would like to point to the possibility that the regression of parathyroid hyperplasia presented by Dr Terawaki et al. may be mediated by VDR upregulation induced by calcimimetics [11], which may facilitate the inhibitory effect of maxicalcitol on PTH secretion and parathyroid cell proliferation.

Therefore, the effect of calcimimetics on the regression of parathyroid hyperplasia, either directly or indirectly, remains unclear. To elucidate these issues, we are currently conducting a prospective clinical trial, which we hope will uncover the antiproliferative effect of calcimimetics on parathyroid hyperplasia in dialysis patients.

Conflict of interest statement. None declared.

Hirotaka Komaba1, Motoko Tanaka2 and Masafumi Fukagawa1

1 Division of Nephrology and Kidney Center, Kobe University School of Medicine, Kobe 2 Department of Nephrology Akebono Clinic, Kumamoto, Japan

References

  1. Fukagawa M, Yumita S, Akizawa T, et al. Cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients. Nephrol Dial Transplant (2008) 23:328-a–335.[Abstract/Free Full Text]
  2. Terawaki H, Nakano H, Takeguchi F, et al. Regression of parathyroid gland swelling by treatment with cinacalcet. Nephrol Dial Transplant. in press.
  3. Drueke T, Martin D, Rodriguez M. Can calcimimetics inhibit parathyroid hyperplasia? Evidence from preclinical studies. Nephrol Dial Transplant (2007) 22:1828–1839.[Free Full Text]
  4. Goto S, Komaba H, Fukagawa M. Pathophysiology of parathyroid hyperplasia in chronic kidney disease: preclinical and clinical basis for parathyroid intervention. NDT Plus (2008) 1(Suppl_3):iii2– iii8.
  5. Fukagawa M, Okazaki R, Takano K, et al. Regression of parathyroid hyperplasia by calcitriol-pulse therapy in patients on long-term dialysis. N Engl J Med (1990) 323:421–422.[Web of Science][Medline]
  6. Fukagawa M, Kitaoka M, Yi H, et al. Serial evaluation of parathyroid size by ultrasonography is another useful marker for the long-term prognosis of calcitriol pulse therapy in chronic dialysis patients. Nephron (1994) 68:221–228.[Web of Science][Medline]
  7. Shiizaki K, Hatamura I, Negi S, et al. Percutaneous maxacalcitol injection therapy regresses hyperplasia of parathyroid and induces apoptosis in uremia. Kidney Int (2003) 64:992–1003.[CrossRef][Web of Science][Medline]
  8. 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]
  9. Colloton M, Shatzen E, Miller G, et al. Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism. Kidney Int (2005) 67:467–476.[CrossRef][Web of Science][Medline]
  10. Mizobuchi M, Hatamura I, Ogata H, et al. Calcimimetic compound upregulates decreased calcium-sensing receptor expression level in parathyroid glands of rats with chronic renal insufficiency. J Am Soc Nephrol (2004) 15:2579–2587.[Abstract/Free Full Text]
  11. Rodriguez M, Almaden Y, Canadillas S, et al. The calcimimetic R-568 increases vitamin D receptor expression in rat parathyroid glands. Am J Physiol Renal Physiol (2007) 292:F1390–F1395.[Abstract/Free Full Text]
  12. Chin J, Miller SC, Wada M, et al. Activation of the calcium receptor by a calcimimetic compound halts the progression of secondary hyperparathyroidism in uremic rats. J Am Soc Nephrol (2000) 11:903–911.[Abstract/Free Full Text]
  13. Mizobuchi M, Ogata H, Hatamura I, et al. Activation of calcium-sensing receptor accelerates apoptosis in hyperplastic parathyroid cells. Biochem Biophys Res Commun (2007) 362:11–16.[CrossRef][Web of Science][Medline]

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H. Komaba and M. Fukagawa
Regression of parathyroid hyperplasia by calcimimetics--fact or illusion?
Nephrol. Dial. Transplant., March 1, 2009; 24(3): 707 - 709.
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