Clinical Endocrinology (1977) 7, Suppl., 151s-158s.

THE EFFECT OF DIALYSATE CALCIUM CONCENTRATION AND la-HYDROXYVITAMIN D, O N SKELETAL CALCIUM LOSS A N D HYPERPARATHYROIDISM IN HAEMODIALYSIS PATIENTS R.J. W I N N E Y , P. T O T H I L L , J.S. R O B S O N , S . R . A B B O T , G.P. L I D G A R D , E.H.D. C A M E R O N , M.A. S M I T H J.N. M A C P H E R S O N A N D J.A. S T R O N G Medical Renal Unit, University Departments of Medicine and Medical Physics Edinburgh Royal Infirmary, Regional Hormone Laboratory, I 2 Bristo Place, Edinburgh and Departments of Medicine and Medical Physics, Western General Hospital, Edinburgh, Scotland

SUMMARY

The response of hyperparathyroidism and skeletal calcium loss in haemodialysis patients to treatment with la-hydroxyvitamin D3 and a dialysate calcium concentration of 1.375mmol/l was compared with the response to treatment with a dialysate calcium concentration of 1.375 or 1.75 mmol/l alone over a 6 month period. In patients treated with la-hydroxyvitamin D3 there was a significant rise in plasma calcium associated with a significant fall in plasma alkaline phosphatase and plasma parathyroid hormone as well as resolution of sub-periosteal erosions. In these patients there was a significant rise in the calcium content of the forearm assessed by neutron activation analysis in comparison to patients treated with a dialysate calcium concentration of 1.75 or 1.375 mmol/l alone. In patients treated with a dialysate calcium concentration of 1.375 or 1.75 mmol/l alone there was no s i p f i c a n t change in the plasma calcium, alkaline phosphatase or parathyroid hormone after 6 months and in these patients subperiosteal erosions either did not change or became worse. No significant difference in the response in these two groups was observed. This study indicates that treatment of haemodialysis patients with 1a-hydroxyvitamin D3 is significantly more effective than treatment with a dialysate calcium concentration of 1.375 or 1.75 mmol/l alone in preventing progression of hyperparathyroidism and skeletal calcium loss.

Correspondence: Dr R. J . Winney, Medical Renal Unit, Royal Infxmary, Edinburgh EH3 9YW, Scotland.

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152s

R. J. Winney et al.

The concentration of calcium in the dialysis fluid influences both parathyroid hormone (FTH) secretion and bone mineral loss in haemodialysis patients (Bone er ul., 1972; Goldsmith & Johnson, 1973; Bouillon er ul., 1975). On the basis of such evidence it has been suggested that use of a high dialysate calcium may delay progression of renal osteodystrophy (Coldsmith & Johnson, 1973). However, th~sis not successful in all patients (Regan eral., 1976). The recent availability of synthetic active metabolites of vitamin D3 has renewed interest in the treatment of renal osteodystrophy. In most haemodialysis patients treated with 1ahydroxyvitamin D3 (1 a-OHD3) there has been improvement in hyperparathyroidism and bone mineralisation (Junor er al., 1976; Rerides er al., 1976) as well as a rise in skeletal calcium content (Catto er al., 1975; Naik eral., 1976). However, in some patients treatment with IaaHD:, has been associated with either no change, or deterioration in renal osteodystrophy (Naik eral., 1976;Pierides e f al., 1976;Winney er al., 1977). The present study compares the response of hyperparathyroidism and skeletal calcium loss t o ' treatment with la-OHD3 and a dialysate calcium concentration of 1.375 mmol/l with the response to treatment with a dialysate calcium concentration of 1.375 or 1.75 mmol/l alone. In patients treated with laOHD3, the dialysate calcium concentration was reduced to 1.375mmol/I since in a previous study (Winney e l a/., 1977), use of la-OHD3 in patients treated with a dialysate calcium concentration of 1.75 mmol/l and a normal dietary calcium was associated with hypercalcaemia. PATIENTS AND METHODS The patients were aged 26-58 years (mean 41 years) and had been established on haemodialysis for 2-1 1 years (mean 4.5 years). Pnor to this study, dialysis in all patients was conducted with a dialysate calcium concentration of 1.75 rnmol/l and magnesium of 0.7Smmol/l. The diet contained 70g of protein, 800mg (90mmol) of calcium and 1 l 0 0 m g (35.5 mmol) of phosphorus daily. No patient had previously been treated with vitamin D but in all patients aluminium hydroxide was given by mouth if necessary in an attempt to maintain the pre-dialysis plasma phosphate in the range I .6-2 mmol/l. Twenty-one patients were randomly allocated to one of three groups. Group 1 continued treatment with a dialysate calcium concentration of 1.75 mmol/l. Two patients failed to attend for study leaving five patients in t h l s group. Group 2 contained seven patients in whom the dialysate calcium concentration was reduced to 1.375mmol/l. Group 3 also contained seven patients in whom the dialysate calcium concentration was also reduced to 1.375mmol/l, but who were additionally treated with la-OHD3 in an initial dose of 2 pg daily. No other aspects of treatment were altered in any group. Blood w a s taken before and 6 months after the changes in treatment for analysis of plasma calcium, phosphate, magnesium and alkaline phosphatase as well as for assay of plasma parathyroid hormone (PTH); all blood being taken immediately before a dialysis treatment. The plasma calcium, phosphate and alkaline phosphatase were monitored more frequently in patients treated with la-OHD3. At the same times, skeletal radiographs were obtained and the calcium content of the non-fistula forearm was measured by neutron activation analysis using a pair of "'Cf sources (Smith er al., 1976). Neutron activation analysis was performed on three separate occasions both before and 6 months after the changes in treatment. The change in calcium counts in the forearm at 6 months was then calculated and expressed as a percentage of the initial counts.

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Dialysate calcium and 1a-hydroxyvitamin D 3

FTH was measured by radioimmunoassay using a bovine standard (I.R.P. 71/324), and an antiserum (CP anti bovine AS 2 11/32) which has predominately N-terminal specificity (Woo & Singer, 1974; Franchimont & Heynen, 1976) but has been shown to react also with the C - t e d n a l portion of PTH (Barling et d . , 1974). The normal range for plasma calcium was 2.1 2-2.62 mmol/l, plasma phosphate 0.8-1.4 mmol/l, and plasma magnesium 0.74-0.96mol/l. The upper h i t of normal for alkaline phosphatase was lOOu/l and for Pl"H 0.2pg/l. Statistical analysis of all data was made using non-parametric methods.

RESULTS The mean values of plasma calcium, phosphate and magnesium as well as the number of patients with subperiosteal erosions (SPE) on hand radiographs before and 6 months after the changes in treatment are shown in Table 1 . Figs 1-3 show the results of plasma alkaline phosphatase, PTH, and the change in calcium counts in the forearm at 6 months expressed as a percentage of the initial counts. All patients had normal plasma protein concentrations both before and 6 months after the changes in treatment. Before the changes in treatment, plasma calcium, phosphate, magnesium alkaline phosphatase and PTH did not differ significantly in the three groups (Table 1 and Figs 1 and 2). In the majority of patients the plasma calcium was in the upper part of the normal range, PTH was high (Fig. 2) and a proportion of patients in each group had a high alkaline phosphatase of bone origin (Fig. 1 ) and SPE (Table 1 ) .

D,,

1.75

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1-375

1.375

la OH D,

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350

1350

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= t 0

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a.

50

5

0

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0

l

o 6monlhs

0

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0 6mon1hs

1 0

Fig. 1 . Plasma akaline phosphatase (u/l) before and 6 months after changes in treatment in the three groups of patients. The upper limit of the normal range is indicated by the interrupted line rDca = dialysate calcium).

2.49i0.31 2.53i0.19

0.5-2

1.375 1.375

0

2.46iO.31 1.78i0.17*

2.56i0.17

6 months

Plasma calcium (mmol/l)

2.6St0.11

la43HD3 (rdday)

1.7s

Dialysate calcium (mmol/l)

2.1i0.33 1.8f0.49

1.53i0.58

0

1.64i0.37* 1.68i0.46

1.83iO.43

6 months

Plasma phosphate (mmol/l)

1.38i0.14 1.32io.1

1.37i0.14

0

3 2

2

1.3 lt0.09 1.42i0.14 1 -37i0.12

0

months

2 (in 1 worse) 4 0

6

SPE (number of patients)

6 months

Plasma magnesium (mmol/l)

Table 1. Plasma calcium, phosphate, magnesium (mean i I S D ) and numbers of patients with subperiosteal erosions (SPE) on hand radiographs before and after 6 months after changes in treatment

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4

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Dialysate calcium and 1a-hydroxyvitamin D 3 1.375

1.375

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-25 -2

- 1.5 -I

-0 5

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oL

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6 months

-J0

Fig. 2. Plasma parathyroid hormone (pg/l) before and 6 months after the changes in treatment in the three groups of patients. The upper limit of the normal range is indicated by the interrupted line (DQ = dialysate calcium).

After 6 months there was n o significant change in plasma calcium, magnesium, alkaline phosphatase of PTH in Groups 1 and 2 (Table 1 and Figs 1 and 2). There was a significant fall in plasma phosphate in Group 2 but not in Group 1 (Table 1). The changes in individual patients were variable, but both alkaline phosphatase and PTH tended to either rise or remain unchanged. In these patients SPE either did not change or became worse (Table 1). No significant difference between the changes in any measured parameter in these two groups could be detected. In contrast, in patients treated with la-OHD3 there was a significant rise in plasma calcium (Table 1) associated with a significant fall in alkaline phosphatase (P< 0.05) (Fig. 1) and PTH (P< 0.05) (Fig. 2). After 6 months the plasma alkaline phosphatase was above normal in only two patients but in five of the seven patients plasma PTH was still hgher than normal. There was no significant change in plasma phosphate or magnesium in these patients. In the two patients with SPE there was complete resolution after 6 months treatment. Both the rise in plasma calcium and the fall in plasma PTH in t h s group were significantly greater than in the other two groups (P< 0.05) and the fall in alkaline phosphatase was significantly greater than in Group 2 (P< 0.05). In the patients treated with la-OHD3 there was a consistent rise in calcium counts using neutron activation analysis which was significantly greater than the change in calcium counts both in Group 1 (P

The effect of dialysate calcium concentration on 1alpha-hydroxyvitamin D3 on skeletal calcium loss and hyperparathyroidism in haemodialysis patients.

Clinical Endocrinology (1977) 7, Suppl., 151s-158s. THE EFFECT OF DIALYSATE CALCIUM CONCENTRATION AND la-HYDROXYVITAMIN D, O N SKELETAL CALCIUM LOSS...
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