Skip Navigation


NDT Advance Access originally published online on December 22, 2008
Nephrology Dialysis Transplantation 2009 24(3):707-709; doi:10.1093/ndt/gfn717
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
24/3/707    most recent
gfn717v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Komaba, H.
Right arrow Articles by Fukagawa, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Komaba, H.
Right arrow Articles by Fukagawa, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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


Regression of parathyroid hyperplasia by calcimimetics—fact or illusion?

Hirotaka Komaba and Masafumi Fukagawa

Division of Nephrology and Kidney Center, Kobe University School of Medicine, Kobe, Japan

Correspondence and offprint requests to: Masafumi Fukagawa, Division of Nephrology and Kidney Center, Kobe University School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Tel: +81-78-382-6500; Fax: +81-78-382-6509; E-mail: fukagawa{at}med.kobe-u.ac.jp

Keywords: calcimimetics; cinacalcet; parathyroid hyperplasia; secondary hyperparathyroidism

Secondary hyperparathyroidism is one of the most common and serious complications of chronic kidney disease (CKD). The main factors responsible for excessive synthesis and secretion of parathyroid hormone (PTH) include phosphate retention, hypocalcaemia and calcitriol deficiency resulting from decreased kidney function [1,2]. Sustained hypersecretion of PTH is associated with an increase in the parathyroid gland size, initially leading to diffuse parathyroid hyperplasia. Subsequently, some cells in the parathyroid glands proliferate in a monoclonal growth pattern, and the enlarged glands exhibit an advanced type of nodular hyperplasia [3]. In the course of parathyroid hyperplasia, both calcium-sensing receptors (CaSR) and vitamin D receptors (VDR) are progressively down-regulated [4,5], which results in diminished responsiveness of parathyroid glands with nodular hyperplasia to active vitamin D treatment.

Conversely, whether regression of parathyroid hyperplasia can occur has remained a matter of discussion. Regression of parathyroid hyperplasia has been reported in rare cases of spontaneous infarction of the glands [6,7]. In addition, enhanced apoptosis of parathyroid cells has been observed in diffuse hyperplasia after kidney transplantation, suggesting the possibility of regression in the long term [8].

In the past, the capacity of calcitriol therapy to induce regression of parathyroid hyperplasia had been a matter of debate. In a study of oral calcitriol pulse therapy, given to chronic haemodialysis patients, we observed a significant decrease in the mean ± SD volume of parathyroid glands (from 0.87 ± 0.32 to 0.51 ± 0.23 cm3) after 12 weeks of treatment, with a concomitant significant reduction in intact PTH levels [9]. In contrast, Quarles et al. failed to observe a decrease in the parathyroid gland size after 36 weeks of intermittent intravenous or oral calcitriol treatments [10]; the mean ± SD gland volume was 1.9 ± 0.6 and 2.1 ± 0.7 cm3 before and 3.3 ± 0.8 and 2.3 ± 0.8 cm3 after oral and intravenous calcitriol therapy, respectively. The reduction in serum intact PTH observed in their study was relatively mild. The discrepancy between these two studies may be attributed to a more severe degree of hyperparathyroidism observed in the latter, as compared to the former study. We also reported that the long-term outcome after calcitriol pulse therapy was dependent on parathyroid change, and that patients with one or more glands >0.5 cm3 became refractory to calcitriol pulse therapy [11].

Taken together, these findings suggest that the degree of parathyroid hyperplasia can be an important determinant for regression in response to calcitriol therapy, and that 0.5 cm3 is approximately the critical size. This concept is supported by the histological analysis of surgically removed parathyroid glands, which revealed that most of the glands exceeding 0.5 g exhibited nodular formations [3]. Notably, regression of advanced nodular hyperplasia can be induced only by direct injection of calcitriol or its analogues into the glands [12].

In this context, the next question is whether the calcimimetic agent cinacalcet, which has become available only recently, is capable of inducing regression of parathyroid hyperplasia in CKD patients [13]. Calcimimetic agents allosterically increase the sensitivity of CaSR to extracellular calcium ions, thereby lowering PTH secretion [14,15]. Theoretically, if PTH hypersecretion is sufficiently suppressed by cinacalcet in the long term, regression of hyperplastic glands will be induced; however, little clinical data exist regarding the actual regression of parathyroid hyperplasia by cinacalcet treatment.

In this issue of the journal, Meola et al. report the effect of cinacalcet treatment on the size of hyperplastic parathyroid glands in haemodialysis patients [16]. Nine patients received 30–120 mg cinacalcet in conjunction with conventional treatment for 24–30 months. Serum intact PTH levels decreased significantly from 1196 ± 381 to 256 ± 160 pg/ml. In glands with a baseline volume <500 mm3, the mean ± SD volume of glands decreased significantly from 233 ± 115 to 102 ± 132 mm3. However, in glands with a baseline volume >500 mm3, the mean ± SD gland volume did not decrease (1036 ± 1062 versus 837 ± 1290 mm3). Interestingly, cystic degeneration and a decrease in vascular supply were also observed in several glands during cinacalcet treatment (Figure 1).


Figure 1
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Schematic representation of the postulated morphological effect of cinacalcet on the hyperplastic parathyroid gland. Cinacalcet may potentially induce regression of parathyroid hyperplasia, as characterized by morphological changes, including reduced gland size, hypovascularization and cystic degeneration [16]. Although the precise mechanism of these phenomena is unclear, it is theoretically possible that the degree of reduction in PTH levels by cinacalcet treatment or the type of hyperplasia (i.e. diffuse or nodular hyperplasia) is an important determinant for regression of hyperplastic glands. These possibilities should be examined by further clinical studies.

 
This study is the first to suggest that cinacalcet treatment may induce regression of parathyroid hyperplasia in CKD patients whose gland volume is not >0.5 cm3 at treatment initiation. In support of this finding, another case of parathyroid size regression in response to cinacalcet treatment has been recently reported [17]. Although these observations are promising, they need to be confirmed by studies in larger numbers of patients. Moreover, the precise mechanism involved in the reduction of the parathyroid gland size remains unclear.

Mizobuchi et al. recently demonstrated that high concentrations of calcimimetics induce apoptosis in parathyroid cells from uraemic rats in vitro [18]. In contrast, several investigators have failed to detect apoptosis in parathyroid cells in vivo [19,20]. Chin et al. demonstrated the possibility of regression of parathyroid hyperplasia, but the reduction in parathyroid volume was attributed to a decrease in cell volume but not in total cell number [21]. More recently, Lomonte et al. evaluated the oxyphil/chief cell ratio of glands excised from haemodialysis patients, suggesting that cinacalcet may, at least theoretically, induce apoptosis in chief cells of hyperplastic parathyroid glands [22]; however, whether the reduction in the parathyroid gland size reported by Meola et al. can be attributed to a decrease in the cell volume or number remains uncertain.

Calcimimetics have also been shown to upregulate CaSR and VDR expressions in uraemia [23,24]. These effects may facilitate the inhibitory effect of calcitriol or its analogues on PTH secretion and parathyroid cell proliferation, thereby leading to the reduction in the parathyroid gland size.

Meola et al. also reported a cystic degeneration of the parathyroid glands during cinacalcet treatment [16]. Such a morphologic change has never been previously reported. Further light microscopy analyses might help to determine whether the cystic degeneration by cinacalcet can be attributed to parathyroid cell apoptosis. The functionality of these cysts is also an important issue [25]. 99mTc-MIBI scintigraphy may help to determine the presence of functioning parathyroid tissues within the cyst wall, since high MIBI uptake has been associated with proliferation of parathyroid cells [26].

Another interesting finding observed in this study was a reduction in the parathyroid gland vasculature during cinacalcet treatment [16]. High blood flow signals evaluated by power Doppler ultrasonography are associated with pathological features of nodular hyperplasia [27]. To date, however, there have been no reports showing a reduction in the parathyroid gland vasculature in CKD patients, except for rare cases associated with spontaneous infarction of the glands [6,7]. Conceptually, it is possible that the reduced vascularity observed in this study was secondary to enhanced apoptosis of parathyroid cells. Another possibility is that cinacalcet directly modulated the parathyroid blood flow through interaction with CaSR in the vasculature; however, effects of calcimimetic-mediated CaSR activation on specific vascular beds in the parathyroid gland have not been demonstrated thus far.

From a clinical point of view, it is important to identify the determinants of the efficacy of cinacalcet for secondary hyperparathyroidism. Cinacalcet has been shown to be efficacious in patients with severe parathyroid over-function [14] and recurrent secondary hyperparathyroidism due to parathyromatosis [28] and kidney graft recipients with persistent hyperparathyroidism [29], suggesting that cinacalcet is capable of controlling a severe type of hyperparathyroidism. However, there are not a few patients who develop severe hyperparathyroidism resistant to cinacalcet therapy and require parathyroidectomy [22]. A recent observational study also suggested that the long-term control of secondary hyperparathyroidism by cinacalcet is difficult in patients with enlarged parathyroid glands [30]. In this context, the finding by Meola et al. is of interest. They reported that significant reductions in parathyroid volume were observed only in glands with a baseline volume <500 mm3, suggesting that the pretreatment parathyroid size is a critical factor in the regression response produced by cinacalcet [16]. Such a possibility may be related to the resistance to long-term cinacalcet therapy in patients with nodular hyperplasia. Further studies are required to prove or disprove that cinacalcet induces regression of severe hyperparathyroidism associated with nodular hyperplasia.

It is also clinically important to clarify whether the reduced parathyroid gland size by cinacalcet therapy can be interpreted as reduced functionality of the gland. In the study of Meola et al., however, withdrawn of cinacalcet resulted in a rebound of intact PTH levels, even in those who had shown marked reduction in parathyroid volume [16]. This is in line with the fact that in kidney transplant recipients, interruption of cinacalcet has been shown to result in an immediate re-increase in serum PTH levels following its administration for 26 weeks [29]. Moreover, to the best of our knowledge, there are no clinical data showing that after long-term cinacalcet treatment the dose of the drug could be progressively reduced due to normalization of the parathyroid gland size. The clinical significance of the reduced parathyroid size by cinacalcet therapy should be examined by further clinical studies.

In conclusion, the demonstration by Meola et al., based on a study in small number of dialysis patients, that parathyroid gland volume can regress in response to cinacalcet treatment must still be considered as inconclusive. It clearly raises the question of the morphological changes induced in parathyroid tissue by this therapy. Larger studies should be conducted to confirm the reported promising effects and their clinical meaning in the treatment of CKD patients with secondary hyperparathyroidism.

Conflict of interest statement. M.F. has received lecture fees and a grant from Kyowa Hakko Kirin, Co. Ltd, Japan, and was a member of advisory committee on clinical trials of cinacalcet in Japan. H.K. has no interest to declare.

(See related article by M. Meola et al. Long-term treatment with cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe secondary hyperparathyroidism. Nephrol Dial Transplant 2009; 24: 982–989.)



   References
Top
 References
 

  1. Drueke TB. Cell biology of parathyroid gland hyperplasia in chronic renal failure. J Am Soc Nephrol (2000) 11:1141–1152.[Free Full Text]
  2. Fukagawa M, Nakanishi S, Kazama JJ. Basic and clinical aspects of parathyroid hyperplasia in chronic kidney disease. Kidney Int (2006) 70(Suppl_102):S3–S7.
  3. Tominaga Y, Tanaka Y, Sato K, et al. Histopathology, pathophysiology, and indications for surgical treatment of renal hyperparathyroidism. Semin Surg Oncol (1997) 13:78–86.[CrossRef][Web of Science][Medline]
  4. Kifor O, Moore FD, Wang P, et al. Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab (1996) 81:1598–1606.[Abstract]
  5. Fukuda N, Tanaka H, Tominaga Y, et al. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest (1993) 92:1436–1442.[Web of Science][Medline]
  6. Tanaka M, Tominaga Y, Sawatari E, et al. Infarction of mediastinal parathyroid gland causing spontaneous remission of secondary hyperparathyroidism. Am J Kidney Dis (2004) 44:762–767.[CrossRef][Web of Science][Medline]
  7. Komaba H, Takeda Y, Abe T, et al. Spontaneous remission of severe hyperparathyroidism with normalization of the reversed whole PTH/intact PTH ratio in a haemodialysis patient. Nephrol Dial Transplant (2008) 23:1760–1762.[Free Full Text]
  8. Taniguchi M, Tokumoto M, Matuo D, et al. Persistent hyperparathyroidism in renal allograft recipients: vitamin D receptor, calcium-sensing receptor, and apoptosis. Kidney Int (2006) 70:363–370.[CrossRef][Web of Science][Medline]
  9. 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]
  10. Quarles LD, Yohay DA, Carroll BA, et al. Prospective trial of pulse oral versus intravenous calcitriol treatment of hyperparathyroidism in ESRD. Kidney Int (1994) 45:1710–1721.[Web of Science][Medline]
  11. 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]
  12. 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]
  13. 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]
  14. Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med (2004) 350:1516–1525.[Abstract/Free Full Text]
  15. 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) 23:328–335.[Abstract/Free Full Text]
  16. Meola M, Petrucci I, Barsotti G. Long-term treatment with cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe secondary hyperparathyroidism. Nephrol Dial Transplant (2009) 24:982–989.[Abstract/Free Full Text]
  17. Terawaki H, Nakano H, Takeguchi F, et al. Regression of parathyroid gland swelling by treatment with cinacalcet. Nephrol Dial Transplant (2009) 24:691–692.[Free Full Text]
  18. 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]
  19. 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]
  20. 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]
  21. 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]
  22. Lomonte C, Vernaglione L, Chimienti D, et al. Does vitamin D receptor and calcium receptor activation therapy play a role in the histopathologic alterations of parathyroid glands in refractory uremic hyperparathyroidism? Clin J Am Soc Nephrol (2008) 3:794–799.[Abstract/Free Full Text]
  23. 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]
  24. 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]
  25. Ujiki MB, Nayar R, Sturgeon C, et al. Parathyroid cyst: often mistaken for a thyroid cyst. World J Surg (2007) 31:60–64.[CrossRef][Web of Science][Medline]
  26. Custódio MR, Montenegro F, Costa AF, et al. MIBI scintigraphy, indicators of cell proliferation and histology of parathyroid glands in uraemic patients. Nephrol Dial Transplant (2005) 20:1898–1903.[Abstract/Free Full Text]
  27. Onoda N, Kurihara S, Sakurai Y, et al. Evaluation of blood supply to the parathyroid glands in secondary hyperparathyroidism compared with histopathology. Nephrol Dial Transplant (2003) 18(Suppl 3):iii34–iii37.[Abstract/Free Full Text]
  28. Eriguchi R, Umakoshi J, Tominaga Y, et al. Successful treatment of inoperable recurrent secondary hyperparathyroidism with cinacalcet HCl. NDT Plus (2008) 1:218–220.[Free Full Text]
  29. Serra AL, Savoca R, Huber AR, et al. Effective control of persistent hyperparathyroidism with cinacalcet in renal allograft recipients. Nephrol Dial Transplant (2007) 22:577–583.[Abstract/Free Full Text]
  30. Tanaka M, Nakanishi S, Komaba H, et al. Association between long-term efficacy of cinacalcet and parathyroid gland volume in haemodialysis patients with secondary hyperparathyroidism. NDT Plus (2008) 1:iii49–iii53.[Abstract/Free Full Text]
Received for publication: 12.11.08
Accepted in revised form: 28.11.08


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
24/3/707    most recent
gfn717v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Komaba, H.
Right arrow Articles by Fukagawa, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Komaba, H.
Right arrow Articles by Fukagawa, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?