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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2003  |  Volume : 14  |  Issue : 2  |  Page : 158-164
The Use of Alphacalcidol Intravenously in Hemodialysis Patients: Experience from Bahrain

1 Consultant Nephrologist, Salmaniya Medical Complex, Bahrain
2 Chief Resident, Salmaniya Medical Complex, Bahrain
3 Consultant in Biochemistry, Salmaniya Medical Complex, Bahrain
4 Technologist in Biochemistry, Salmaniya Medical Complex, Bahrain

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While the effects of vitamin D, one-alphahydroxycholecalciferol (alphacalcidol) administered intravenously on the serum levels of parathormone (PTH) and calcium in dialysis patients have been well studied in the past few years, no detailed studies were conducted in patients from this part of the world. We studied nine patients (four men and five women) who received this drug for 12 weeks. The mean age of the patients was 54.4 ± 19.8 (range: 23-81) years and the duration on dialysis was 40.1 ± 15.6 (range: 18-62) months. The patients were selected on the basis of baseline serum intact PTH values of more than twice the upper limit of normal; all of the patients were on oral alphacalcidol, which was stopped before the study. Alphacalcidol was administered during the last fifteen minutes of each dialysis session, three times per week. The dose of the drug was upregulated weekly to a maximum of 6µg per session according to the degree of suppression of PTH and/or the development of hypercalcemia. The results showed a significant decrease of the mean serum PTH from baseline of 77.58 ± 49.13 to 41.87 ± 48.87 pmol/L (p<0.02). Serum phosphate 2.01 ± 0.27 and calcium 2.38 ± 0.25 did not change significantly from baseline . None of the patients developed local or systemic adverse reaction to the injection; only one patient developed hypercalcemia requiring short interruption of the vitamin D with later resumption at a lower dose. In conclusion, alphacalcidol administered intravenously is effective and safe in hemodialysis patients.

Keywords: Hemodialysis, Parathyroid hormone, Alphacalcidol, Suppression

How to cite this article:
Al-Arrayed S, Seshadri R, Nagalla S, Al- Khayyat MH. The Use of Alphacalcidol Intravenously in Hemodialysis Patients: Experience from Bahrain. Saudi J Kidney Dis Transpl 2003;14:158-64

How to cite this URL:
Al-Arrayed S, Seshadri R, Nagalla S, Al- Khayyat MH. The Use of Alphacalcidol Intravenously in Hemodialysis Patients: Experience from Bahrain. Saudi J Kidney Dis Transpl [serial online] 2003 [cited 2022 Jan 18];14:158-64. Available from: https://www.sjkdt.org/text.asp?2003/14/2/158/33025

   Introduction Top

Secondary hyperparathyroidism and renal osteodystrophy are common abnormalities in chronic renal failure due to the deficiency of 1-alpha hydroxycholecalciferol (alphacalcidol, D3) as a result of decreased kidney mass and the decreased 1-alpha hydroxylase, the enzyme responsible for the synthesis of this active form of vitamin D in the kidney.1, 25-dihydr­oxycholecalciferol (calcitriol), which is form­ed by further hydroxylation in the liver, can correct hypocalcemia in addition to the direct suppression of the parathormone (PTH) pro­duction through the vitamin D receptors in the parathyroid gland. [1],[2]

Replacement of this renal hormone has become a cornerstone in the management of osteodystrophy in the hemodialysis patients. Vitamin D in the form of alphacalcidol could be usefully administered either orally or intra­venously. However, the intravenous route probably delivers more adequate amount of the drug to effectively suppress PTH produc­tion with fewer episodes of hypercalcemia and hyperphosphatemia and need for parathy­roidectomy. [3],[4],[5] Several studies, short-term and long-term, have been published on the use of intravenous vitamin D in secondary hyperpar­athyroidism. [2],[6],[7],[8],[9] However, data from this part of the world on the effect of such therapy on the levels of PTH are lacking. It is important to establish the response to such therapy in different populations because of the variability in response to pharmacological agents seen in different races.

We report in this study our experience of the effectiveness and safety of the intravenously administered alphacalcidol in our hemodia­lysis population.

   Patients and Methods Top

Adult Bahraini patients with end-stage renal disease on hemodialysis were included in the study. The inclusion criteria included a minimum of one-year period on hemodialysis and serum parathyroid hormone level more than two times the upper limit of normal. The exclusion criteria included hemoglobin level less than 9.0 gm/dl, history of parathyroid­ectomy, significant bone disease, and serum calcium greater than 2.9 mmol/L or Ca X P product greater than 5.9 mmol 2 /L 2 .

There were four men and five women who satisfied the criteria of the study. They all consented to take part in the study. Their ages ranged between 23 and 81 years with a mean of 54.4 ± 19.8 years. The duration on dialysis ranged between 18 months and 62 months with a mean of 40.1 ± 15.6 months. The cause of end-stage renal failure was diabetic nephropathy in five patients, chronic glome­rulonephritis in two and unknown in the remaining two. One patient had hepatitis type B viral infection with normal serum trans­aminase level.

All the patients were on bicarbonate dialysate mode, dialysate calcium of 1.75 mmol/L, steam sterilized polysulfone membrane hol­low fiber dialyzers (Fresenius) and three hours three times a week dialysis sessions.

Oral alphacalcidol was discontinued before the commencement of the study in all the patients. Calcium supplement in the form of calcium carbonate was continued. Phosphate binders as calcium carbonate or aluminum hydroxide was continued. Diet restricted in phosphorus was reinforced by renal dietitian.

Injectable Alphacalcidol (One-Alpha, Leo Pharmaceutical Products, Denmark) was administered during the last fifteen minutes of each dialysis session through the venous return line of the extracorporeal circuit. Any adverse reaction was reported and docu­mented. The initial dose of alphacalcidol was based on the approved dosage at the con­sensus conference on this subject at theannual meeting of the American Society of Nephrology, 1994. [10]

The study patients were categorized as having mild to moderate hyperparathyroidism if the intact PTH level was less than 66 pmol/L, moderate to severe if PTH level was between 66 and 132 pmol/L and severe if it exceeded 132 pmol/L.

A dose of 0.5 to 1.0 µg was used initially in patients with mean baseline PTH level less than 66 pmol/L (pg/ml X 0.11 = pmol/L) and 2 µg dose injectable alphacalcidol was used in those with higher levels.

Weekly estimation of calcium, phosphorus, PTH and serum alkaline phosphates was performed and the dose of alpha-calcidol was upregulated in order to achieve maximal suppression of PTH production. The maximum dose received by any patient was not more than 6 µg per session. Treatment was interrupted if calcium level reached 3 mmol/L or more and restarted at a lower dose after normal level was attained.

The level of hemoglobin was followed up to avoid anemia due to repeated blood sampling. Serum intact PTH was estimated by immunoassay based on the principle of chemiluminescence using the kit (Immulite 2000 Intact PTH, DPC). The detection limit of the assay was 0.1 pmol/L The normal reference range was 0.99 to 6.05 pmol/L and the coefficient of variation was 2.52% for PTH concentration less than 263 pmol/L.

The normal reference range of the bio­chemical tests was as follows: Calcium (Ca) 2.13-2.63 mmol/L, Phosphorus (P) 0.8-1.4 mmol/L, Alkaline phosphatase (ALP) 50­136 u /L.

Statistical analysis

Results were expressed as the mean ± SD. The Student's t test was used to compare means. P value <0.05 was considered significant.

   Results Top

Nine patients, four males and five females, satisfied the criteria to enter the study protocol. At the start of the study, six of the nine patients had mild to moderate hyperparathyroidism. The remaining three patients, one man and two women, had moderate to severe hyperparathyroidism with baseline PTH level of 73.86, 166.8 and >263 pmol/L, respectively. One patient had mild hypocalcemia and another had mild hypercalcemia. All the patients had hyper­phosphatemia but their Ca X P products were all less than 5.9 mmol 2 /L 2 . Elevated Alkaline phosphatase (ALP) level was noted in four patients.

There was no local or systemic adverse reaction to the injection of alphacalcidol and all patients tolerated the doses well. The laboratory tests were followed for two more weeks after completion of the study period.

During the study, there was no significant change in the mean serum calcium (2.38 ± 0.25 to 2.40 ± 0.22 mmol/L,[Figure - 1].Despite the reduction of phosphorus in the diet and the use of phosphate binders, significant hyperpho­sphatemia persisted [Figure - 2]. An initial rise followed by a steady fall of ALP was seen [Figure - 3]. There was an impressive decrease of the mean serum PTH (77.58 ± 49.13 to 41.87 ± 48.87 pmol/L (p<0.02), [Figure - 4]). The dose response curve of alphacalcidol to PTH was linear with a steady fall of PTH level followed by a quick rebound rise at two weeks after discontinuing vitamin D injection. Suppre­ssion of PTH secretion was observed before the rise in serum calcium level. The percentage change in suppression of PTH level after twelve weeks of therapy compared to base line varied from 15.04% to 83.6%. This variability in response among the subjects was not apparently related to the initial level of PTH or of phosphorus.

As side effects of the vitamin D therapy, one patient developed hypercalcemia (serum Ca > 3 mmol/L) requiring interruption of injection treatment for two weeks, after which the vitamin D was restarted at a lower dose and the serum Ca was maintained below 3.0 mmol/L. Another patient had persistently high Ca X P product without hypercalcemia, al­though there was suppression of PTH secretion.

   Discussion Top

This short-term prospective study of the effect of injectable vitamin D on secondary hyperparathyroidism in nine hemodialysis pat­ients shows significant suppression of PTH secretion without producing hypercalcemia in the majority of subjects. Alphacalcidol admi­nistered intravenously was found to be safe and well tolerated during this period. The duration of our study was similar to the study by Sverker et al. [11] The rebound rise in the PTH level within two weeks after discon­tinuing injection therapy suggests that the suppressive effect was short lived and might require long-term therapy for the benefit to continue. [12]

Effective and early suppression of hyperpa­rathyroidism would lead to improvement of bone disease that is present in a large number of patients at the time of starting dialysis. Vitamin D therapy causes regression of para­thyroid hyperplasia by inducing cellular apoptosis in the gland. [13],[14],[15],[16] In our study, the suppression of PTH was observed before the rise of serum calcium level, which was similar to the findings of other studies. [1],[17],[18],[19]

During the first four weeks of our study, there was a rise in the alkaline phosphatase level before a fall was observed in paradox to the fall in the PTH level; most likely due to the stimulating action of vitamin D on the osteoblasts. On long-term treatment with active derivatives of vitamin D, an "escape" pheno­menon could be observed in the levels of serum alkaline phosphatase. [20],[21] Furthermore, there is the risk of adynamic bone disease with too much suppression of parathyroid gland. [22],[23]

In our study, both patients who had severe hyperparathyroidism were found to have enlarged parathyroid glands on ultrasono­graphy; however, there was no resistance to the suppressive effect of alphacalcidol. The high PTH levels may relapse requiring long­term vitamin D therapy, especially if there was nodular monoclonal hyperplasia of para­thyroid glands, due possibly to genetic mutation. [24],[25]

In the early stages of chronic renal failure, there is deficiency of calcitriol and an abnor­mality in calcium sensor receptors (CaR). Parathyroid hormone level starts increasing when GFR falls to 60 ml/min. [26] Later, the increased serum phosphorus becomes an additional factor as glomerular filtration rate (GFR) falls to 20 ml/min. Hyperphosphat­emia is a major obstacle to the suppressive effective of vitamin D on the parathyroid glands by decreasing the expression of CaR. [27],[28],[29],[30],[31]

The successful control of hyperphosphatemia and its direct stimulant action on the parathy­roid glands depends on the coordinated effort of the committed nephrologist, dialysis nurse, renal dietitian and social worker by giving dietary education and reinforcing that advice periodically. Prolongation of the duration of dialysis sessions and the use of noncalcemic, non-aluminum based phosphate binders would be beneficial in the long-term control of serum phosphorus level. Novel phosphate binders like trivalent-iron based salts, lanthanum salts and polyallylamine (sevelamer hydrochloride) and phosphate transport inhibitor (niceritorol) are likely to become established in clinical practice. [32] Non-calcemic forms of vitamin D analogs like oxacalcitriol and paricalcitol and calcimimetic agents would probably replace conventional alphacalcidol and calcitriol. [33]

We conclude that injectable 1-alphahydroxycholecalciferol is an effective and safe treat­ment modality for secondary hyperparathyro­idism due to uremia in hemodialyzed patients. Longer duration of therapy may be required to maintain this benefit.

   Acknowledgement Top

The authors wish to thank the dialysis unit nurses and the staff of the biochemistry department of Salmaniya Medical Complex for their enthusiastic participation. Further­ more, we extend our gratitude to M/s Leo Pharmaceutical Products for the supply of alphacalcidol injections for this study.

   References Top

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6.Oettinger CW, Oliver JC, Macon EJ. The effects of calcium carbonate as the sole phosphate binder in combination with low calcium dialysate and calcitriol therapy in chronic hemodialysis patients. J Am Soc Nephrol 1992;3:995-1001.  Back to cited text no. 6  [PUBMED]  
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9.Rodriguez M, Felsenfeld AJ, Dunlay R, Williams C, Pederson JA, Llach F. The effect of long-term calcitriol admini­stration on parathyroid function in hemodialysis patients. Am Soc Nephrol 1991;2:1014-20.  Back to cited text no. 9    
10.Fernandez E, Llach F. Guidelines for dosing of intravenous calcitriol in dialysis patients with hyperparathyroidism. Nephrol Dial Transplant 1996;3:96-101.  Back to cited text no. 10    
11.Ljunghall S, Althoff P, Fellstrom B, et al. Effects on serum parathyroid hormone of intravenous treatment with alphacalcidol in patients on chronic hemodialysis. Nephron 1990;55:380-5.  Back to cited text no. 11    
12.Dressler R, Laut J, Lynn RI, Ginsberg N. Long-term high dose intravenous calcitriol therapy in end-stage renal disease patients with severe secondary hyperparathyroidism. Clin Nephrol 1995;43(5): 324-31.  Back to cited text no. 12    
13.Ruedin P, Rizzoli R, Slosman D, Leski M, Bonjour J. Effects of oral calcitriol on bonemineral density in patients with end stage renal failure. Kidney Int 1994;45:245-52.  Back to cited text no. 13    
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15.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(6): 421-2.  Back to cited text no. 15    
16.Fukagawa M, Wi H, Kurokawa K. Calcitriol induces apoptosis of hyerplastic parathyroid cells in uremia. J Am Soc Nephrol 1991;2:635.  Back to cited text no. 16    
17.Silver J, Russele J, Sherwood LM. Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hor­mone in isolated bovine parathyroid cells. Proc Natl Acad Sci USA 1985;82:4270-3.  Back to cited text no. 17    
18.Cantley LK, Russele J, Lettieri D, Sherwood LM. 1, 25 Dihydroxyvitamin D3 suppresses parathyroid hormone secretion from bovine parathyroid cells in tissue culture. Endocrinology 1985; 117:2114-9.  Back to cited text no. 18    
19.Russel J, Lettieri D, Sherwood LM. Suppression by 1,25 (OH)2D3 of transcrip­tion of the pre-proparathyroid hormone gene. Endocrinology 1986; 119:2864-6.  Back to cited text no. 19    
20.Coburn JW, Brickman AS, Sherrard DJ, et al. Clinical efficacy of 1,25 (OH) 2 D3 in renal osteodystrophy. In: AW Norman, K Schaefer, JW Coburn, HF DeLuca, D Fraser, H Grigoleit, D von Herrath, eds. Vitamin D: biochemical, chemical and clinical aspects relating to calcium metabolism. Berlin: Walter deGruyter 1977:657-66.  Back to cited text no. 20    
21.Cundy TF, Hamdy NA, Kanis JA. Factors modifying the secretion and action of parathyroid hormone in renal failure. Contrib Nephrol 1988;64:5-15.  Back to cited text no. 21  [PUBMED]  
22.Cannata-Andia JB. Hypokinetic azotemic osteodystrophy. Kidney Int 1998;54:1000-16.  Back to cited text no. 22    
23.Malluche HH, Monier-Faugere MC. Risk of adynamic bone disease in dialyzed patients. Kidney Int Suppl 1992;438:S62-7  Back to cited text no. 23    
24.Fukagawa M, Kitaoka M, Kurokawa K. Resistance of the parathyroid glands to vitamin D in renal failure. Implications for medical management.Kidney Int Suppl 997; 62: S60-4.  Back to cited text no. 24    
25.Falchetti A, Bale AE, Amorosi A, et al. Progression of uremic hyperparathyroidism involves allelic loss on chromosome 11. J Clin Endocrinol Metab 1993;76:139-44.  Back to cited text no. 25  [PUBMED]  [FULLTEXT]
26.Llach F, Velasquez Forero F. Secondary hyperparathyroidism in chronic renal failure: Pathogence and clinical aspects. Am J Kidney Dis 2001;38(Suppl 5):S20-33.  Back to cited text no. 26    
27.Brown AJ, Ritter CS, Finch JL, Slatopolsky EA. Decreased calcium sensing receptor expression in hyperplastic parathyroid glands of uremic rats: role of dietary phosphate. Kidney Int1999;55 (4):1284-92.  Back to cited text no. 27    
28.Arik N, Basoglu T, Sungur C, et al. Hyperph­osphatemia: a serious limiting factor preven­ting the possible benefit from intravenous calcitriol therapy. Nephron 1999;82:77-8.  Back to cited text no. 28    
29.Delmez JA, Slatopolsky E. Hyperphospha­temia: Its consequences and treatment in patients with chronic renal disease. Am J Kidney Dis 1992;19:303-17.  Back to cited text no. 29  [PUBMED]  
30.Reiss E, Canterbury JM, Bercovitz MA, Kaplan EL. The role of phosphate in the secretion of parathyroid hormone in man. J Clin Invest 1970;49:2146-9.  Back to cited text no. 30  [PUBMED]  [FULLTEXT]
31.Drueke TB. Control of secondary hyperpara­thyroidism by vitamin D derivatives. Am J Kidney Dis 2001;37(Suppl 2):S58-61.  Back to cited text no. 31    
32.Hergesell O, Ritz E. Phosphate binders on iron basis: a new perspective Kidney Int Suppl 1999; 73:S42-5.  Back to cited text no. 32    
33.Nemeth EF, Bennett SA. Tricking the parathyroid gland with novel calcimimetic agents.Nephrol Dial Transplant 1998;13: 1923-5.  Back to cited text no. 33  [PUBMED]  [FULLTEXT]

Correspondence Address:
Sameer Al-Arrayed
Department of Nephrology, Salmaniya Medical Complex, P.O. Box 12, Manama
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