Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
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 ISI Web of Science
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 arrow Search for citing articles in:
ISI Web of Science (8)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Shiizaki, K.
Right arrow Articles by Akizawa, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shiizaki, K.
Right arrow Articles by Akizawa, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Nephrol Dial Transplant (2003) 18: III42-III46
© 2003 European Renal Association-European Dialysis and Transplant Association

Original Article

Effect of percutaneous calcitriol injection therapy on secondary hyperparathyroidism in uraemic patients

Kazuhiro Shiizaki1,, Shigeo Negi1, Masahide Mizobuchi1, Ikuji Hatamura2, Nobuhiko Narukawa1, Toshifumi Sakaguchi1, Yukiko Kitabata1, Shinji Sumikado1 and Tadao Akizawa1

1 Center of Blood Purification Therapy and 2 The First Department of Pathology, Wakayama Medical University, Wakayama, Japan



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. The impetus to develop percutaneous calcitriol injection therapy (PCIT) was the lack of therapeutic tools to treat secondary hyperparathyroidism (2HPT) resistant to medical therapy.

Methods. Nine dialysis patients resistant to intravenous calcitriol or calcitriol analogues underwent daily PCIT 5–10 times consecutively. The PCIT involved the injection of a volume of calcitriol equal to that of the enlarged parathyroid glands (PTGs) under ultrasonographic guidance. All patients had follow-up intravenous calcitriol after PCIT.

Results. The serum intact PTH concentration was markedly reduced following PCIT and was maintained for 12 weeks with intravenous calcitriol without significant changes in serum adjusted calcium and phosphorus concentrations. All patients tolerated PCIT without serious adverse events. Serum bone alkaline phosphatase concentrations and the volume of the enlarged PTGs were also significantly reduced.

Conclusion. PCIT is a safe and effective treatment, which may also suppress parathyroid hyperplasia and improve bone turnover for refractory 2HPT.

Keywords: calcitriol; end-stage renal disease (ESRD); interventional ultrasonography; renal osteodystrophy; secondary hyperparathyroidism



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
New agents for the control of secondary hyperparathyroidism (2HPT), including calcium (Ca)-free phosphorus (P) binders, active vitamin D derivatives and calcimimetics, have been developed recently [1–4]. However, parathyroidectomy–autotransplantation (PTx–AT) is still necessary to control severe 2HPT resistant to medical therapy. General anaesthesia is necessary for PTx–AT, which can be dangerous for high-risk patients with pulmonary or cardiovascular disorders, especially as repeated operations may be needed in cases of recurrent or persistent hyperparathyroidism.

The development of ultrasonography has made it possible to perform percutaneous ethanol injection therapy (PEIT) in patients with refractory 2HPT, and this is now known to be as effective as PTx–AT [5]. However, there are some adverse side effects, such as laryngeal palsy, the difficulty of PTx–AT following failed PEIT and the necessity for specialists in all these techniques and procedures.

Calcitriol (1,25-dihydroxy vitamin D3), which is the most active metabolite of vitamin D, controls parathyroid gland (PTG) growth and suppresses the synthesis and secretion of parathyroid hormone (PTH) [6,7]. It has been reported that intravenous administration of calcitriol suppresses PTH dose dependently [3] but, for the many patients with advanced 2HPT that is resistant to intravenous calcitriol, effective and safe therapeutic tools, such as direct injection of calcitriol into the PTG (PCIT), are developed.

In the present study, the effects of PCIT on serum concentrations of PTH, Ca, P and bone markers, and on the volume of the PTG were investigated.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Case studies
Nine patients undergoing regular haemodialysis for end-stage renal disease (ESRD) participated in the present study (Table 1Go). All patients had severe 2HPT resistant to more than 3 months of intravenous administration of vitamin D derivatives. The study was approved by the local medical ethics committee, and informed consent was obtained from each patient.


View this table:
[in this window]
[in a new window]
  		Table 1.  Background characteristics of the patients

 

Percutaneous calcitriol injection therapy (PCIT)
The enlarged PTGs were examined by ultrasonography (SSD 5500, Aloka, Tokyo, Japan) and their sizes were estimated by 3D measurement ({pi}/6xaxbxc) [8]. Calcitriol injection was performed using the same type of needle as used for PEIT (KM-N type, Hakko, Tokyo, Japan) [5]. Under ultrasonographic guidance, the needle was inserted into the centre of the PTG. If the volume of the PTG was >0.5 cm3, we made several insertions in different sites of the PTG in order to saturate it with calcitriol solution.

The PCIT was performed once a day for 5–10 consecutive days (6.56±1.51) (mean±SD). The injected volume of calcitriol solution (1 µg/ml) was estimated to be same as the volume of each gland (mean dose of calcitriol: 2.33±1.00 µg per one injection, 15.7±8.29 µg per total injections). There was good correlation between dosage and the total volume of the PTG (r2=0.838, P<0.01) (Figure 1Go). In patients with multiple enlarged PTGs, all detectably enlarged glands were treated by PCIT at the same time, even if they existed bilaterally.



View larger version (10K):
[in this window]
[in a new window]
  		Fig. 1.  Relationship between injected calcitriol dose and total PTG volume before PCIT (n=9) (injected calcitriol dose=total PTG volume+0.733, r2=0. 838, P<0.01).

 
After PCIT, all patients were treated with intravenous calcitriol at the end of every haemodialysis session. The initial dose, 1 µg per session, was altered according to the serum Ca and intact PTH (i-PTH) concentrations, which were measured periodically (dose of calcitriol 4 and 12 weeks after PCIT: 0.86±0.48 and 0.86±0.63 µg per haemodialysis session, respectively).

Laboratory measurements and radiological examinations
Concentrations of serum i-PTH, adjusted Ca (calculated by Payne formula) [9], P, bone alkaline phosphatase (BALP) and intact bone Gla protein (i-BGP) were obtained for all patients before and after the series of PCIT. In seven of the patients, these data were also obtained 12 weeks after PCIT.

Serum i-PTH concentration was measured by the two-antibody method using Allegro® i-PTH (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA). Serum BALP and i-BGP levels were measured by precipitation with wheat germ lectin using an Iso-ALP test kit (Roche Diagnostics GmdH, Mannheim, Germany) and by immunoradiometric assay using a BGP-IRMA kit (Yuka-Medias, Tokyo, Japan), respectively. Concentrations of serum Ca, P and albumin were determined with an automated analyser (TBA-200FR, Toshiba, Tokyo, Japan). Total PTG volumes were calculated using ultrasonography before and, in seven patients, at 12 weeks after PCIT. Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA) (DPX-L, GE Lunar, Madison, WI, USA). Technetium-99m methoxyisobutylisonitrile imaging (99mTc-MIBI) or thallium-201-technetium-99 m subtraction scintigraphy (Tl-Tc) of the PTG was carried out for all patients in order to rule out the existence of ectopic PTG.

Statistical analysis
Data were expressed as mean±SD. Data were analysed by simple correlation or Student's t-test, and a P value <0.05 was considered statistically significant.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Patient characteristics
Table 1Go shows relevant laboratory data of the patients before PCIT. The mean serum i-PTH concentration was 716±311 pg/ml, indicating severe 2HPT in spite of intravenous vitamin D therapy. The mean adjusted Ca and P concentrations were 10.8±0.61 and 6.11±1.76 mg/dl, respectively, so these patients were diagnosed as refractory 2HPT resistant to medical treatment. In addition, the high concentrations of bone metabolic markers (mean serum BAP and i-BGP levels were 161±74.5 IU/l and 178±108 ng/ml, respectively) and low bone mineral content by DXA (mean Z-score: –1.11±0.68) suggested bone mineral loss because of high turnover bone disease resulting from the 2HPT.

Ectopic PTG was not detected by 99mTC-MIBI or Tl-Tc in any of the patients.

Changes in the laboratory data after PCIT
The PCIT series significantly reduced serum i-PTH concentrations (177±112 pg/ml: P<0.01); the mean reduction rate was 74.3±14.0%. In contrast, serum adjusted Ca and P concentrations did not change significantly throughout the study period (adjusted Ca and P concentrations after PCIT were 11.6±1.06 and 5.84±1.11 mg/dl, respectively) (Figure 2Go). Increased concentrations of serum BALP and i-BGP did not change significantly as a result of PCIT (BALP and i-BGP concentrations after PCIT: 177±78.5 IU/l and 248±210 ng/ml, respectively).



View larger version (17K):
[in this window]
[in a new window]
  		Fig. 2.  Changes in serum i-PTH, adjusted calcium (Ca) and phosphorus (P) concentrations before and after PCIT (n=9). After PCIT, serum i-PTH concentrations were significantly reduced, but serum adjusted Ca and P concentrations did not change significantly. (*P<0.01 vs before PCIT).

 

Serum i-PTH concentration 12 weeks after PCIT
Twelve weeks after PCIT, serum i-PTH concentrations in seven patients showed a significant reduction compared with values before PCIT (761±340 vs 474±223 pg/ml: P<0.05) (Figure 3Go); however, serum adjusted Ca and P concentrations did not change significantly (10.8±0.67 vs 10.6±0.88 mg/dl and 6.14±1.88 vs 5.69±1.12 mg/dl, respectively).



View larger version (15K):
[in this window]
[in a new window]
  		Fig. 3.  Change in serum i-PTH concentration 12 weeks after PCIT (n=7). The serum i-PTH concentrations were significantly decreased 12 weeks after PCIT (P<0.05 vs before PCIT).

 

Effects of PCIT on bone metabolic markers
In seven patients, bone markers tended to decrease as a result of PCIT and subsequent intravenous calcitriol treatment. The reduction in serum BALP concentration was significant 12 weeks after PCIT (176±78.2 vs 127±67.0 IU/l; P<0.05) (Figure 4Go).



View larger version (18K):
[in this window]
[in a new window]
  		Fig. 4.  Changes in serum bone alkaline phosphatase (BALP) and intact bone Gla protein (i-BGP) concentrations before and 12 weeks after PCIT (n=7). Serum BALP concentrations were significantly decreased 12 weeks after PCIT (P<0.05 vs before PCIT).

 

Effect of PCIT on PTG volume
Total PTG volumes were significantly reduced 12 weeks after PCIT compared with volumes before PCIT (1.78±0.96 vs 1.31±1.20 cm3; P<0.05) (Figure 5Go).



View larger version (9K):
[in this window]
[in a new window]
  		Fig. 5.  Changes in total PTG volume before and 12 weeks after PCIT (n=7). Total PTG volume was significantly decreased by PCIT and the follow-up calcitriol intravenous therapy (*P<0.05 vs before PCIT).

 



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Secondary hyperparathyroidism from chronic renal failure causes many complications, including uraemic bone disease [10,11], which are detrimental to quality of life and prognosis; therefore, control of 2HPT is essential for such patients.

In Japan, intravenous calcitriol and 22-oxacalcitriol are used to suppress parathyroid function in patients with mild or moderate 2HPT [2]. However, some patients with 2HPT become resistant to these conventional therapies because of their poor effect on PTH reduction and/or complications of hypercalcaemia, so PCIT was developed to treat severe 2HPT resistant to medical therapies.

Kitaoka et al. reported the efficacy and safety of direct injection of calcitriol into the PTG three times a week for 2 weeks [12]. However, the follow-up period of their study was only 6 weeks and the changes in bone markers caused by PCIT were not investigated. In the present study, injection times for each patient were adjusted to suppress PTH concentrations sufficiently, so the mean serum i-PTH concentrations after PCIT were reduced to 177±112 pg/ml (the mean reduction rate was 74.3±14.0%). In contrast, serum adjusted Ca and P concentrations did not change significantly during the treatment with PCIT. Moreover, serum i-PTH concentrations 12 weeks after PCIT were significantly reduced compared with before PCIT, without significant changes in serum Ca and P. These results suggest that 2HPT was significantly suppressed by PCIT, and the response of the PTG cells to intravenous calcitriol therapy had recovered. This suppression of 2HPT might improve the high turnover bone disease caused by 2HPT as evidenced by a significant reduction in serum BALP concentrations.

We also confirmed a significant reduction of PTG volume 12 weeks after PCIT, which is another finding supporting its ability to suppress 2HPT. Fukagawa et al. reported a significant decrease in PTG volume after 12 weeks of oral calcitriol pulse therapy and hypothesized that the apoptosis was induced in PTG cells by the high concentration of calcitriol [8]. The in vivo induction of apoptosis in parathyroid cells by percutaneous maxacalcitol injection therapy (PMIT) has also been reported [13]. The regression of enlarged PTG after PCIT is presumed to result from the decreased number of parathyroid cells by apoptosis; however, the precise mechanism for this process remains under investigation. It was reported that the level of vitamin D receptors (VDRs) in PTG was significantly reduced in advanced nodular hyperplasia, and this is considered to be the pathogenesis of the PTG resistance to vitamin D therapy [14]. Bolus oral or intravenous calcitriol administration is reported to improve resistance to calcitriol by up-regulation of the VDR in PTG cells [15–17]. Thus, up-regulation of VDR by PCIT may be another mechanism of the suppression of 2HPT.

In summary, we clarified that PCIT and subsequent intravenous calcitriol administrations suppress 2HPT, high turnover bone disease and PTG hyperplasia without remarkable adverse events, including hypercalcaemia. PCIT is another therapeutic option for severe 2HPT and an alternative to PEIT or PTx–AT.



   Acknowledgments
 
The authors thank Dr Masafumi Kitaoka (Division of Endocrinology and Metabolism, Showa General Hospital, Tokyo, Japan) for training in parathyroid intervention techniques under ultrasonography.



   Notes
 
Correspondence and offprint requests to: Kazuhiro Shiizaki, Center of Blood Purification Therapy, Wakayama Medical University, 811-1 Kimiidera Wakayama 641-0012, Japan. Email: shiizaki{at}wakayama-med.ac.jp Back



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Slatopolsky EA, Burke SK, Dillon MA et al. RenaGel®, a nonabsorbed calcium- and aluminium-free phosphate binder, lowers serum phosphorus and parathyroid hormone. Kidney Int 1999; 55:299–307[CrossRef][Web of Science][Medline]
  2. Akizawa T, Suzuki M, Akiba T et al. Long-term effect of 1,25-dihydroxy-22-oxavitamin D3 on secondary hyperparathyroidism in hemodialysis patients: one-year administration study. Nephrol Dial Transplant 2002;17
  3. Koshikawa S, Akizawa T, Kurokawa K et al. Clinical effect of intravenous calcitriol administration on secondary hyperparathyroidism. Nephron 2002; 90:413–423[CrossRef][Medline]
  4. Goodman WG, Hladik GA, Turner SA et al. The calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol 2002; 13:1017–1024[Abstract/Free Full Text]
  5. Kitaoka M, Fukagawa M, Ogata E, Kurokawa K. Reduction of functioning parathyroid cell mass by ethanol injection in chronic dialysis patients. Kidney Int 1994; 46:1110–1117[Web of Science][Medline]
  6. Cozzolino M, Lu Y, Finch J et al. p21WAF1 and TGF-{alpha} mediate parathyroid growth arrested by vitamin D and high calcium. Kidney Int 2001; 60:2109–2117[CrossRef][Web of Science][Medline]
  7. Naveh-Many T, Rahamimov R, Livni N, Silver J. Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate and vitamin D. J Clin Invest 1995; 96:1786–1793
  8. Fukagawa M, Okazaki R, Takano K et al. Regression of parathyroid hypertrophy by calcitriol-pulse therapy in patients on long-term dialysis. N Engl J Med 1990; 323:421–422[Web of Science][Medline]
  9. Payne RB, Little AJ, Williams RB, Milner JR. Interpretation of serum calcium in patients with abnormal serum proteins. Br Med J 1973; 15:643–646
  10. Rao DS, Shin MS, Mohini R. Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 1993; 328:171–175[Abstract/Free Full Text]
  11. Ganesh S, Stack A, Levin N et al. Association of elevated serum PO4, CaxPO4 product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001; 12:2131–2138[Abstract/Free Full Text]
  12. Kitaoka M, Fukagawa M, Fukuda N et al. Direct calcitriol injections into enlarged parathyroid glands in chronic dialysis patients with severe parathyroid hyperfunction. Nephrology 1995; 1:563–567
  13. Shiizaki K, Hatamura I, Negi S et al. Clinical effects and changes of parathyroid cells induced by percutaneous maxacalcitol injection therapy (PMIT) in patients with secondary hyperparathyroidism (2HPT). J Am Soc Nephrol 2002; 13:194A
  14. 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; 92:1436–1443
  15. Slatopolsky E, Weerts C, Thielan J et al. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest 1984; 74:2136–2143
  16. Levine S, Song M. Pharmacokinetics and efficacy of pulse oral versus intravenous calcitriol in hemodialysis patients. J Am Soc Nephrol 1996; 7:488–496[Abstract]
  17. Patel R, Ke Q, Hsu H. Regulation of calcitriol receptor and mRNA in normal and renal failure rats. Kidney Int 1994; 45:1020–1027[Web of Science][Medline]

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


This article has been cited by other articles:


Home page
 NDT PlusHome page
K. Shiizaki, I. Hatamura, S. Negi, E. Nakazawa, R. Tozawa, S. Izawa, T. Akizawa, and E. Kusano
Cellular changes following direct vitamin D injection into the uraemia-induced hyperplastic parathyroid gland
NDT Plus, August 1, 2008; 1(suppl_3): iii42 - iii48.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
K. Shiizaki, I. Hatamura, S. Negi, T. Sakaguchi, F. Saji, I. Imazeki, E. Kusano, T. Shigematsu, and T. Akizawa
Highly Concentrated Calcitriol and its Analogues Induce Apoptosis of Parathyroid Cells and Regression of the Hyperplastic Gland Study in Rats
Nephrol. Dial. Transplant., December 21, 2007; (2007) gfm850v1.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
T. Drueke, D. Martin, and M. Rodriguez
Can calcimimetics inhibit parathyroid hyperplasia? Evidence from preclinical studies
Nephrol. Dial. Transplant., July 1, 2007; 22(7): 1828 - 1839.
[Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
K. Shiizaki, N. Hayakawa, I. Imazeki, I. Hatamura, T. Okada, S. Negi, T. Sakaguchi, T. Shigematsu, and T. Akizawa
Binding of highly concentrated maxacalcitol to the nuclear vitamin D receptors of parathyroid cells
Nephrol. Dial. Transplant., April 1, 2007; 22(4): 1078 - 1086.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
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 ISI Web of Science
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 arrow Search for citing articles in:
ISI Web of Science (8)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Shiizaki, K.
Right arrow Articles by Akizawa, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shiizaki, K.
Right arrow Articles by Akizawa, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?