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Nephrol Dial Transplant (2003) 18: III53-III57
© 2003 European Renal Association-European Dialysis and Transplant Association

Original Article

Time course of change in calcium x phosphorus product after percutaneous ethanol injection therapy

Fumihiko Koiwa, Takeshi Hasegawa, Ichiro Kojima and Terukuni Ideura

Division of Nephrology, Department of Internal Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Percutaneous ethanol injection therapy (PEIT) effectively suppresses PTH secretion, but the change in the serum calcium and phosphorus product (CaxP) after PEIT has not been fully evaluated.

Methods. Twenty-seven haemodialysis patients with severe secondary hyperparathyroidism (2HPT) were divided into two groups according to their intact PTH (i-PTH) concentrations 6 months after PEIT: (i) effective (E) group, i-PTH concentration <360 pg/ml; and (ii) non-effective (N) group i-PTH ß360 pg/ml. The changes in serum calcium and phosphorus concentrations and the CaxP were recorded for the following 2 years under post-PEIT medical treatment with oral calcitriol or intravenous 22-oxacalcitriol (OCT).

Result. In the E group, the i-PTH concentrations decreased to <300 pg/ml 1 year after PEIT (801±302 to 280±134 pg/ml), then increased to 435±201 pg/ml at 2 years. Serum calcium concentration did not show any significant change except for a transient reduction at 1 month after PEIT. The CaxP decreased for 1 year (from 66.3±15.3 to 56.2±10.3 mg2/dl2; P<0.05), in agreement with the course of phosphorus concentration, and continued to be <60 mg2/dl2 up to 2 years after PEIT. The CaxP tended to decrease more with OCT than oral calcitriol. In the N group, calcium and CaxP increased significantly at 6 months after PEIT and remained at a high value.

Conclusion. Treatment with PEIT suppresses serum PTH concentration as well as CaxP in the long term.

Keywords: calcium and phosphorus product; ectopic calcification; hypercalcaemia; hyperphosphataemia; percutaneous ethanol injection therapy (PEIT); secondary hyperparathyroidism



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
One of the major adverse effects of secondary hyperparathyroidism (2HPT) as a complication of chronic renal failure is that it causes a disorder of calcium and bone metabolism.

The frequency of hypercalcaemia induced by vitamin D pulse therapy increases depending on the progression of hyperparathyroidism. In recent years, the clinical efficacy of 22-oxacalcitriol, a vitamin D analogue with a low calcaemic action, has been reported [1]. However, even with this new tool, it is difficult to reduce the incidence of hypercalcaemia, resulting in a continuous increase of the calcium and phosporus product (CaxP). A high CaxP is related to the calcification of the coronary artery [2] and cardiac valve [3] and, according to a large-scale study conducted in the USA, a raised CaxP is associated with a high mortality risk in haemodialysis patients [4]. Furthermore, in a cohort study of >1000 Japanese patients who underwent parathyroidectomy (PTx), it was shown that calcification of vessels and valves is irreversible [5]. For effective control of 2HPT, administration of a large dose of active vitamin D and calcium supplement as a phosphorus binder is widely practised, but this can increase CaxP, which accelerates the ectopic vascular and cardiac valve calcification. Therefore, the ultimate goal in the treatment of 2HPT should be changed from prevention of renal osteodystrophy to prevention of cardiac risk, thus making it important to manage calcium and phosphorus metabolism.

It is difficult to resolve advanced 2HPT disorders relating to calcium and phosphorus metabolism by medical treatment alone, making PTx the treatment of choice. In recent years, percutaneous ethanol injection therapy (PEIT) has been accepted as an effective therapeutic tool for the management of advanced 2HPT [6], and it has been reported that PEIT results in long-term reduction of parathyroid hormone (PTH) concentration [7]. However, the effect of PEIT on calcium and phosphorus concentrations and their product has not been fully evaluated.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Patients
Twenty-seven patients (13 women, 14 men) with severe 2HPT regularly undergoing haemodialysis without a history of PTx participated in the present study. The mean age of the patients was 58±10 years (range 35–74 years), and their mean duration of haemodialysis was 197±78 months (range 49–357 months). The patients were referred to Showa University Fujigaoka Hospital and underwent PEIT from August 1997 to June 2000. The causes of chronic renal failure were nephrosclerosis in one, chronic glomerulonephritis in 20 and unknown origin in six, but none of the patients had chronic renal failure from diabetic nephropathy. The patients were classified into two groups based on the rate of decrease in intact PTH (i-PTH) concentration 6 months after PEIT. The group in whom the treatment was effective (E) showed a reduction in i-PTH level to <360 pg/ml within 6 months following PEIT. In the other group, the treatment was classified as non-effective (N) as the i-PTH concentration remained >=360 pg/ml 6 months after PEIT.

Criteria for PEIT intervention were as follows: (i) serum PTH concentration >400 pg/ml at physiological calcium concentration; (ii) refractory to medical therapy such as calcitriol pulse therapy; (iii) at least one parathyroid gland >10 mm in diameter with internal blood supply shown by Doppler ultrasonography; and (iv) evidence of high turnover bone disease together with a relatively high serum total alkaline phosphatase (ALP) concentration.

Written informed consent was obtained from all participating patients.

PEIT and follow-up protocol
Ultrasonographic examination was performed using an SSA-270 A Colour Doppler Ultrasonography unit (Toshiba Medical Co. Ltd, Tokyo, Japan) with a 7.5 MHz scanner. The injection comprised 90% ethanol with 1% lidocaine, and was administered under ultrasonic conditions without local anaesthesia. The maximum volume of ethanol injected was ~80% of the estimated volume of the parathyroid gland, calculated from the dimensions of gland. Glands measuring >1 cm in diameter and with a blood supply were selected for PEIT, and the success of treatment was evaluated as elimination of the blood supply.

All the patients had follow-up medical therapy after the first PEIT treatment with either oral calcitriol pulse therapy or intravenous 22-oxacalcitriol therapy. The target ranges were: i-PTH, 150–360 pg/ml and adjusted serum Ca concentration <11 mg/dl. The initial dose of oral calcitriol was 1.0–2.0 µg twice per week, and that of 22-oxacalcitriol was 5–10 µg three times per week. In the present study, further PEIT was not carried out after the initial series of PEIT. The E group was divided into two subgroups according to the type of medication administered after PEIT: oral calcitriol (n=12), and 22-oxacalcitriol (n=9).

Serum PTH concentration was measured by two-antibody radioimmunoassay using an Allegro PTH kit (Nichols Institute, San Juan Capistrano, CA, USA). Serum albumin, calcium, phosphate and ALP concentrations were measured using an autoanalyser (Hitachi model 7350 type, Hitachi Electronics Co. Ltd, Tokyo, Japan).

All data are shown as mean±SD, and statistical analysis was performed using Wilcoxon's non-parametric analysis test and ANOVA; a P-value <5% was regarded as significant.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
There was no difference between the two groups in the number of parathyroid glands detected or the number of glands treated (2.4±0.8 in the E group, 2.2±0.8 in the N group, and 1.6±0.7 in the E group, 1.7±0.5 in the N group, respectively). Before PEIT, the mean total gland volume in the E group was 3.2±2.6 cm3, which was significantly reduced after PEIT to 2.0±2.1 cm3; there was a similar reduction in gland size in the N group (from 5.6±4.7 to 2.7±1.7 cm3). Frequency of treatment was significantly lower in the E group than in the N group (3.2±1.7 vs 5.7±0.8, P<0.01). There were no differences in adjusted Ca, iP, i-PTH and ALP concentrations between the two groups before PEIT (Table 1Go).


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  		Table 1.  Baseline laboratory data in the E and N groups before PEIT

 
In the E group, serum i-PTH concentrations decreased from 801±302 to 321±161 pg/ml 1 month after PEIT, and remained <300 pg/ml (281±134 pg/ml) at 1 year, which was significantly lower than in the N group at 1 year. However, in the E group, the i-PTH concentration increased to 435±201 pg/ml 2 years after PEIT; in the N group, it did not change significantly. In the E group, the serum ALP concentration decreased from 283±113 to 194±57 IU/l 6 months after PEIT and also showed a significant decrease at 1 year. This was not significantly different from the effect observed in the N group (Figure 1Go).



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  		Fig. 1.  Changes in i-PTH (A) and alkaline phosphatase (B) concentrations after PRIT. Open circles, E (effective) group; closed circles, N (non-effective) group. Data are expressed as mean±SD (**P<0.01 and ***P<0.001 vs 0 months. {dagger}P<0.05 and {dagger}{dagger}{dagger}P<0.001 between E vs N group).

 
In the E group, the adjusted serum Ca concentration decreased significantly from 10.4±0.8 to 10.0±0.7 mg/dl at 1 month after PEIT, and remained at ~10.2 mg/dl at 2 years. The serum Pi concentration decreased from 6.3±1.3 to 5.0±1.2 mg/dl 1 month after PEIT and remained <6 mg/dl at 2 years. In the N group, a transient increase in serum Ca concentration was observed 1 year after PEIT. There were no significant changes in phosphorus concentration up to 2 years after PEIT (Figure 2Go).



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  		Fig. 2.  Change in CaxP after PEIT. Open circles, E (effective) group; closed circles, N (non-effective) group. Data are expressed as mean±SD (*P<0.05 and ***P<0.001 vs 0 months, {dagger}P<0.05 between E vs N group).

 
In the E group, CaxP decreased from 66.3±15.3 to 50.0±13.9 mg2/dl2 1 month after PEIT, decreased significantly within the first year, and remained <60 mg2/dl2 (58.0±7.9 mg2/dl2) for 2 years. In the N group, CaxP tended to increase to >60 mg2/dl2 within the first year, but then did not change significantly for 2 years (Figure 3Go).



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  		Fig. 3.  Changes in adjusted calcium (A) and phosphorus (B) concentrations after PEIT. Open circles, E (effective) group; closed circles, N (non-effective) group. Data are expressed as mean±SD (*P<0.05, **P<0.01 and ***P<0.001 vs 0 month, {dagger}P<0.05 between the E vs the N group).

 
The decrease in CaxP was greater when using 22-oxacalcitriol than with oral calcitriol as post-medication therapy, although there was no difference observed in the decrease in PTH concentration between therapies (Figure 4Go).



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  		Fig. 4.  Effect of post-medication on CaxP and i-PTH concentration in the E group. Open circles, 22-oxacalcitriol; closed circles, oral calcitriol. Data are expressed as mean±SD. By ANOVA, P-values of change in CaxP by 22-oxacalcitriol are 0.087; however, there was no significant change in the oral calcitriol group.

 



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
PEIT is widely recognized in Japan as an effective therapy for treatment of 2HPT [6]. In 21 of the present 27 patients (77.8%), serum PTH concentrations decreased to <300 pg/ml 1 year after PEIT; these results are in agreement with those of previous studies [7]. As PTH is recognized as a potential cardiac and vascular toxin, its suppression is essential for the prevention of ectopic calcification [8].

Although the efficacy of PEIT is widely recognized, changes in calcium and phosphorus concentrations after PEIT have been evaluated only recently. In the treatment of advanced 2HPT, the use of active vitamin D and calcium-containing phosphate binders must be minimized because of the occurrence of hypercalcaemia in many cases, which leads to difficulties in management. In the present study, serum calcium and phosphorus concentrations decreased significantly from the target range 1 month after PEIT, as a direct result of the treatment. However, serum calcium concentrations did not change after 1 month post-PEIT; thus, the stability of the serum calcium concentration reflects the effects of active vitamin D supplementation and of the calcium-containing phosphate binder. In the present study, the mean dose of oral calcitriol was 2.5 µg/week, and that of 22-oxacalcitriol was 15 µg/week administered immediately after PEIT; these doses could be increased in many patients depending on the result of PEIT. However, in the present study, serum calcium concentrations did not change over a long period even though the vitamin D dosage was increased after PEIT. Moreover, the dose of the calcium-containing phosphate binder could also be increased after PEIT in some patients, causing a decrease in serum phosphorus concentration, showing that reduction in serum phosphorus concentration can be brought about both directly and indirectly by PEIT. Serum hyperphosphataemia can adversely affect cardiac prognosis [9], as well as accelerate progression of parathyroid hyperplasia and PTH oversecretion, so PEIT is useful in management of HPT.

Serum CaxP was <60 mg2/dl2 up to 2 years after PEIT. It has been reported that the use of vitamin D and high CaxP correlate with calcification in patients with chronic renal failure [10]. A recent study in Japan indicated that CaxP>60 mg2/dl2 significantly correlated with an increased risk of myocardial infarction and cardiac failure [11]. Another large-scale study conducted in the USA reported that CaxP should be <55 mg2/dl2 to prevent vascular disease and cardiac death [12]. To evaluate the effect of the combination of serial PEIT followed by medical therapy commencing after a decrease in PTH concentration in the present study, further PEIT was not performed during the observation period. Five of 21 patients (23.8%) from the E group showed an i-PTH concentration exceeding the target range of <360 pg/ml 1 year after PEIT, and 11 (52.4%) showed this result at 2 years. In the present study, i-PTH concentrations exceeded 400 pg/ml at 2 years after PEIT in spite of the fact that CaxP was <60 mg2/dl2 for 2 years. Our findings show that it is possible to control PTH concentration by this procedure without performing additional PEIT.

By increasing the dose of vitamin D, which increases the PTH level, the CaxP can be increased. Therefore, additional PEIT should be considered if control of the PTH level is insufficient.

The type of active vitamin D compound used as the medical treatment following PEIT has not been fully evaluated. Only oral calcitriol was used until the 1990s; 22-oxacalcitriol and intravenous calcitriol agents have been available in Japan since 2000 and 2001, respectively. The efficacy of oral pulse therapy vs intravenous calcitriol treatment for 2HPT is still under debate [13,14]. Moreover, a comparative long-term trial of the efficacy of intravenous calcitriol and 22-oxacalcitriol on the treatment of 2HPT has not yet been reported. We observed that 22-oxacalcitriol could maintain suppression of serum PTH concentration for up to 1 year without the development of non-physiological hypercalcaemia [1]. In the present study, CaxP tended to decrease for 1 year in the group treated with 22-oxacalcitriol as post-PEIT medication. Based on this result, we suggest that 22-oxacalcitriol is a more effective drug than oral pulse calcitriol because of its low calcaemic action. However, this is only a retrospective, preliminary study; a random prospective study is needed to determine which type of vitamin D compound is most effective for medical therapy following PEIT.

In conclusion, PEIT is a useful approach for suppression of PTH concentration and CaxP, and this suppression can be maintained for up to 2 years by the combination of initial PEIT followed by medical therapy. In addition, 22-oxacalcitriol seems to be effective as a drug for suppression of CaxP, but further study is necessary to confirm this.



   Acknowledgments
 
We thank Drs Kanji Shishido (Kawasaki Clinic), Atsushi Yoshida (Sagami Jyunkan-ki Clinic) and Fumiyoshi Nakayama (Second Eda Clinic) for their help and support.



   Notes
 
Correspondence and offprint requests to: Fumihiko Koiwa, Showa University Fujigaoka Hospital, Division of Nephrology, Department of Internal Medicine 1-30 Fujigaoka, Aoba-ku, Yokohama 227-8501, Japan. Email: f-koiwa{at}sa2.so-net.ne.jp Back



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Akizawa T, Suzuki M, Akiba T et al. Clinical effects of maxacalcitriol on secondary hyperparathyroidism of uremic patients. Am J Kidney Dis 2001; 38 [Suppl 1]:S147–S151[Web of Science][Medline]
  2. Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 34:1478–1483
  3. Ribeiro S, Ramos A, Brandao A et al. Cardiac valve calcification in haemodialysis patients: role of calcium–phosphate metabolism. Nephrol Dial Transplant 1998; 13:2047–2052[Abstract/Free Full Text]
  4. Block GA, Hulbert-Shearon TE, Levin NW et al. Association of serum phosphorus and calciumxphosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998; 31:607–617[Web of Science][Medline]
  5. Tominaga Y, Uchida K, Haba T et al. More than 1000 cases of total parathyroidectomy with forearm autograft for renal hyperparathyroidism. Am J Kidney Dis 2001; 38 [Suppl 1]:S168–S171[Medline]
  6. Kitaoka M, Fukagawa M, Ogata E et al. Reduction of functioning parathyroid cell mass by ethanol injection in chronic dialysis patients. Kidney Int 1994; 46:1110–1117[Web of Science][Medline]
  7. Kakuta T, Fukagawa M, Fujisaki T et al. Prognosis of parathyroid function after successful percutaneous ethanol injection therapy guided by color doppler flow mapping in chronic dialysis patients. Am J Kidney Dis 1999; 33:1091–1099[Web of Science][Medline]
  8. Baczynski R, Massry SG, Kohan R et al. Effect of parathyroid hormones on myocardial energy metabolism in the rat. Kidney Int 1985; 27:718–725[Web of Science][Medline]
  9. Amann K, Gross ML, London GM et al. Hyperphosphatemia: a silent killer of patients with renal failure? Nephrol Dial Transplant 1999; 14:2085–2087[Free Full Text]
  10. Milliner DS, Zinsmeister AR, Lieberman E et al. Soft tissue calcification in pediatric patients with end-stage renal disease. Kidney Int 1990; 38:931–936[Web of Science][Medline]
  11. Japanese Society of Dialysis Therapy. An Overview of Regular Dialysis Treatment in Japan as of December 31, 2001. Japanese Society for Dialysis Therapy, Tokyo, Japan, 2002
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  13. 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]
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F. Koiwa, T. Hasegawa, R. Tanaka, and T. Kakuta
Indication and efficacy of PEIT in the management of secondary hyperparathyroidism
NDT Plus, August 1, 2008; 1(suppl_3): iii14 - iii17.
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