Effect of calcitriol treatment and withdrawal on hyperparathyroidism in haemodialysis patients with hypocalcaemia
Aquiles Jara1,,
Cecilia Chacón1,
Andres Valdivieso1,
Luis Aris1,
Roberto Jalil1 and
Arnold J. Felsenfeld2
1 Department of Nephrology, Hospital Clinico, Pontificia Universidad Catolica de Chile, Santiago, Chile and
2 Department of Medicine, West Los Angeles VA Medical Center and UCLA, Los Angeles, CA, USA
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Abstract
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Background. Calcitriol is used to treat secondary hyperparathyroidism in dialysis patients. For similarly elevated parathyroid hormone (PTH) levels, the PTH response to calcitriol treatment is believed to be better in hypocalcaemic dialysis patients than in dialysis patients with higher serum calcium values. Furthermore, few studies have evaluated the rapidity of the rebound in serum PTH values after prolonged treatment with calcitriol. Our goal was to evaluate (i) the PTH response to calcitriol treatment in hypocalcaemic haemodialysis patients, (ii) the rapidity of rebound in PTH after calcitriol treatment was stopped, and (iii) whether the effect of calcitriol treatment on PTH levels could be separated from those produced by changes in serum calcium and phosphate values.
Methods. Eight haemodialysis patients (29±3 years) with hypocalcaemia and hyperparathyroidism were treated thrice weekly with 2 µg of intravenous calcitriol and were dialysed with a 3.5 mEq/l calcium dialysate. Parathyroid function (PTHcalcium curve) was determined before and after 30 weeks of calcitriol treatment and 15 weeks after calcitriol treatment was stopped.
Results. Pretreatment PTH and ionized calcium values were 907±127 pg/ml and 3.89±0.12 mg/dl (normal, 4.52±0.07 mg/dl). During calcitriol treatment, one patient did not respond, but basal (predialysis) PTH values in the other seven patients decreased from 846±129 to 72±12 pg/ml, P<0.001 and in all seven patients, the decrease exceeded 85%. During the 15 weeks after calcitriol treatment was stopped, a slow rebound in basal PTH values in the seven patients was observed, 72±12 to 375±44 pg/ml. Covariance analysis was used to evaluate the three tests of parathyroid function (0, 30, and 45 weeks), and showed that calcitriol treatment was associated with reductions in maximal PTH values while reductions in basal PTH were affected by ionized calcium and serum phosphate. The basal/maximal PTH ratio and the set point of calcium were associated with changes in ionized calcium.
Conclusions. In haemodialysis patients with hypocalcaemia, (i) moderate to severe hyperparathyroidism responded well to treatment with calcitriol, (ii) reductions in maximal PTH were calcitriol dependent while reductions in basal PTH were affected by the ionized calcium and serum phosphate concentrations, (iii) changes in the basal/maximal PTH ratio and the set point of calcium were calcium dependent, and (iv) the delayed rebound in basal PTH levels after withdrawal of calcitriol treatment may have been due to the long duration of treatment and the marked PTH suppression during treatment.
Keywords: calcitriol; calcium; parathyroid function; parathyroid hormone; phosphate
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Introduction
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Calcitriol is used to treat secondary hyperparathyroidism in dialysis patients. Treatment is generally indicated when intact parathyroid hormone (PTH) levels exceed 400500 pg/ml [14]. Several studies have shown that the failure to control serum phosphate values adversely affects the response to calcitriol treatment [5,6]. The presence of hypercalcaemia in dialysis patients combined with marked elevations of PTH is generally indicative of severe hyperparathyroidism and a poor response to calcitriol treatment. Conversely, despite similarly elevated PTH levels, hypocalcaemic dialysis patients often respond well to treatment with calcitriol. This difference in response to calcitriol treatment could be because the maximal PTH response to hypocalcaemia is less in the hypocalcaemic than in the hypercalcaemic patient suggesting that the hypocalcaemic patient has less severe hyperparathyroidism [7].
Few studies have evaluated the rapidity of the rebound in serum PTH values after prolonged treatment with calcitriol or its active analogues [811]. In previous studies it was reported that PTH values returned to precalcitriol values by 4 weeks after treatment was discontinued [9,11]. Parathyroid function testing, in which the PTH response to the induction of hypo- and hypercalcaemia is studied, has been reported before and after prolonged calcitriol treatment, but not after discontinuation of calcitriol treatment. In such a situation, the maximal PTH response to hypocalcaemia might differ from that of the predialysis (basal) PTH, which is presumably more influenced by the prevailing serum calcium concentration. Moreover, changes in serum PTH, calcium and phosphate values at the three study intervals should allow an evaluation of the effect of calcitriol treatment and those of changes in serum calcium and phosphate on the dynamics of PTH secretion. The goal of the present study was (i) to evaluate the PTH response to calcitriol treatment in hypocalcaemic haemodialysis patients, (ii) to assess the rapidity of rebound in PTH values after calcitriol treatment was stopped, and (iii) to determine whether the effect of calcitriol treatment on PTH values could be separated from those produced by changes in serum calcium and phosphate values.
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Subjects and methods
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Eight haemodialysis patients with hypocalcaemia and moderate to severe secondary hyperparathyroidism were studied. The entry criteria were an ionized calcium
4.35 mg/dl and a predialysis intact PTH level greater than 450 pg/ml, a value which previously was shown to be almost 100% predictive of osteitis fibrosa or mixed bone disease [14]. The mean age of the patients was 29±3 years and the gender distribution was six females and two males. The duration of haemodialysis before study entry was 95±13 months. The mean PTH and ionized calcium values were 907±127 pg/ml and 3.89±0.12 mg/dl respectively; in 11 normal volunteers, the mean ionized calcium concentration was 4.52±0.07 mg/dl (P<0.001). Individual values for age, gender, basal PTH, and ionized calcium are shown in Table 1
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Table 1. Age and sex of patients, dose of calcitriol given during the study, and reason that calcitriol was withheld or dose reduced
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All patients were dialysed at the haemodialysis unit of the Hospital Clinico in Santiago, Chile. The study was approved by the Human Studies Committee at the Hospital Clinico. No patient was diabetic or had received calcitriol previously. The primary phosphate binder was calcium carbonate. Aluminium hydroxide was sometimes used together with calcium carbonate for a short time if the serum phosphate concentration exceeded 7 mg/dl.
At entry patients had parathyroid function testing performed, after which they were started on 2 µg of intravenous calcitriol thrice weekly. After 30 weeks of calcitriol treatment, parathyroid function testing was repeated, after which calcitriol was discontinued and patients were followed up for an additional 15 weeks. After these 15 weeks, parathyroid function testing was repeated.
Before the study, all patients except one were dialysed with a 3.5 mEq/l calcium dialysate. During the 45 weeks of study, all patients were dialysed with a 3.5 mEq/l calcium dialysate for 1213.5 h/week and had Kt/V values greater than 1.25. The dialysate bicarbonate concentration was 36 mEq/l and the dialysate magnesium concentration was 1 mEq/l.
During calcitriol treatment, serum calcium and phosphate measurements were performed weekly. Parathyroid hormone was measured every 4 weeks except for one interval of 6 weeks. If serum calcium was between 11.5 and 12 mg/dl or serum phosphate was between 7 and 8 mg/dl, the calcitriol dose was reduced from 2 to 1 µg after each haemodialysis. If serum calcium was greater than 12 mg/dl or serum phosphate was greater than 8 mg/dl, calcitriol was withheld. When serum calcium decreased to less than 11.5 mg/dl or serum phosphate decreased to less than 7 mg/dl, calcitriol was restarted at 1 µg after each haemodialysis. After calcitriol treatment was discontinued, measurements for PTH, calcium, and phosphate were performed every 3 weeks.
Parathyroid function was performed as has been described previously [6,7,12,13]. To determine maximal PTH secretion and suppression, low (1 mEq/l) and high (4 mEq/l) calcium haemodialyses were performed on separate days within 1 week. From the data obtained during dialysis-induced hypo- and hypercalcaemia, the following criteria were applied: (i) basal PTH was the predialysis PTH level, (ii) maximal PTH was the highest PTH level observed in response to hypocalcaemia and where an additional reduction of the serum calcium did not further increase PTH, (iii) minimal PTH was the lowest PTH level during suppression by hypercalcaemia and where a further increase in the serum calcium did not result in any additional decrease in PTH, (iv) the ratio of basal to maximal PTH was the basal PTH divided by the maximal PTH; this fraction was multiplied by 100, and in normal volunteers is 2025% [14]. By correcting the actual PTH for the overall capacity to produce PTH (maximal PTH), a measure of the relative degree of PTH stimulation is obtained; and (v) the set point of calcium was defined as we have done previously [6,7,12,13] as the serum calcium concentration at which maximal PTH secretion was reduced by 50%; the set point of calcium was also defined by the method of Brown in which the set point is the mid-range of the PTHcalcium curve [14].
Intact PTH (normal, 1065 pg/ml) was measured with an immunoradiometric assay (Nichols, San Juan Capistrano, CA). During studies of parathyroid function, ionized calcium was measured with a selective electrode (Nova 8, Nova Biomedical, Waltham, MA). At all other times, standard laboratory techniques were used to measure serum calcium and phosphate.
Statistics
For comparisons between two groups, the Student t-test was used. Repeated measures analysis of variance (ANOVA) was used for three or more comparisons in the same patient; for a significant ANOVA, the Duncan test was used for inter-group comparisons. Covariance analysis was used to determine the effect of calcitriol treatment on the response variable. If the P value for the covariates was not <0.05, stepwise regression was used to determine the effect of independent variables on a dependent variable. A P value <0.05 was considered significant. Results are shown as the mean±SE.
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Results
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The total calcitriol dose given to each patient during the 30 weeks, the number of times calcitriol was withheld, and the reason for withholding or reducing the dose of calcitriol is shown in Table 1
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Table 2
shows the mean serum calcium, phosphate, and PTH values in the eight patients before calcitriol treatment (week 0), during the 30 weeks of calcitriol treatment, and during the 15 weeks after calcitriol treatment was stopped. As compared to pre-treatment, 30 weeks of calcitriol treatment resulted in a marked decrease in PTH values (P<0.001) and an increase in serum calcium values (P<0.001). Fifteen weeks after calcitriol was stopped, PTH values remained much lower than before calcitriol treatment (P<0.01) while serum calcium values were higher (P<0.01) and those of serum phosphate were not different from values before calcitriol treatment.
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Table 2. Serum PTH, calcium and phosphate values during 30 weeks of calcitriol treatment and the 15 weeks after cessation of calcitriol treatment in the eight study patients
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Because the basal PTH response to calcitriol treatment decreased by greater than 85% in the seven responders to calcitriol treatment, the results in these patients are shown separately in Figure 1
. Repeated measures ANOVA showed that differences were present for PTH (P<0.001) and serum calcium (P<0.001), but not for serum phosphate (P=0.33). The results shown in Figure 1
also suggest that at least after the initial PTH response at 4 weeks, changes in PTH seemed to follow changes in serum calcium and phosphate. For example, PTH values did not change between 4 and 8 weeks as serum calcium levels decreased slightly and serum phosphate levels did not change. The decrease in PTH values between 8 and 12 weeks was associated with an increase in serum calcium and a decrease in serum phosphate values. Between 12 and 26 weeks, PTH levels did not change appreciably despite continued calcitriol treatment. During that time, serum calcium values varied little and serum phosphate values were, in general, greater than 6 mg/dl. Finally, between 26 and 30 weeks, PTH values decreased as those of serum calcium increased and serum phosphate decreased.

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Fig. 1. Serum calcium, phosphate, and PTH values during calcitriol treatment in the seven patients who responded to calcitriol treatment. Shown are the serum calcium (solid line), serum phosphate (broken line), and PTH (bar) values at the times at which pre-dialysis PTH values were measured during the 30 weeks of calcitriol treatment. Mean±SE. a P<0.05 vs 0 weeks, b P<0.05 vs 4, 8 and 22 weeks, and c P<0.05 vs 4 and 8 weeks.
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In Figure 2
, serum calcium, phosphate and PTH values during the 15-week recovery period from calcitriol treatment are shown excluding the one patient who failed to respond to calcitriol treatment. Repeated measures ANOVA showed that differences were present for PTH (P<0.001) and serum calcium (P<0.001), but not for serum phosphate (P=0.12). Three weeks after calcitriol was stopped (33 weeks), both serum calcium and phosphate levels had decreased while PTH values had more than doubled (Figure 2
). For the next 9 weeks, serum calcium values remained in the hypocalcaemic range and essentially did not vary while serum phosphate and PTH values did not change. Between 42 and 45 weeks, serum calcium values increased (Figure 2
). Despite the increase in serum calcium, the PTH value at 45 weeks increased further and was greater than PTH values at 33 and 36 weeks. However, even 15 weeks after calcitriol was stopped, the PTH value remained less than 50% of the precalcitriol value, 375±44 vs 846±129 pg/ml, P<0.01.

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Fig. 2. Serum calcium, phosphate, and PTH values during the 15 weeks after calcitriol was stopped in the seven patients who responded to calcitriol treatment. Shown are the serum calcium (solid line), serum phosphate (broken line), and PTH (bar) values at the times at which predialysis PTH values were measured during the 15 weeks after calcitriol treatment was stopped. Mean±SE a P<0.05 vs 0 weeks, b P<0.05 vs 33, 39 and 42 weeks, and c P<0.05 vs 33 and 36 weeks.
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In Table 3
, the results of parathyroid function testing in the eight patients are shown before calcitriol treatment (0 weeks), after calcitriol treatment (30 weeks), and following the cessation of calcitriol treatment (45 weeks). Calcitriol treatment resulted in an increase in ionized and total calcium levels and a decrease in the ratio of basal/maximal PTH and in basal, maximal and minimal PTH values (0 vs 30 weeks). Fifteen weeks after calcitriol treatment was stopped, ionized and total calcium levels decreased and the ratio of basal/ maximal PTH and basal, maximal, and minimal PTH values increased (45 weeks).
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Table 3. Serum calcium, phosphate and parameters of PTHcalcium curve (parathyroid function) at baseline (0 week), after 30 weeks of calcitriol treatment (30 weeks), and 15 weeks after calcitriol treatment was stopped (45 weeks) in the eight study patients
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In the eight patients who received calcitriol treatment, the mean decrease in basal PTH was 80±12% vs 70±10% for maximal PTH (P=0.004). One patient did not respond, and in that patient basal PTH values before and after calcitriol treatment were 1353 and 1376 pg/ml; the mean weekly serum calcium and phosphate values during the 30 weeks of calcitriol treatment were 8.48±0.07 and 7.12±0.11 mg/dl respectively. The exclusion of that patient resulted in an even greater decrease in basal, maximal, and minimal PTH values and the basal/maximal PTH ratio. In these seven patients, the mean basal PTH after calcitriol treatment (30 weeks) was 72±12 pg/ml; the mean decrease in basal PTH was 91±2% vs 80±2% for maximal PTH (P<0.001). Shown in Figure 3
are the effects of 30 weeks of calcitriol treatment and the discontinuation of calcitriol treatment on the PTH-calcium curve in the seven responders to calcitriol treatment.

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Fig. 3. PTHcalcium curves at 0, 30, and 45 weeks in the seven patients who responded to calcitriol treatment. The PTHcalcium curves obtained before calcitriol treatment (0 weeks), after 30 weeks of calcitriol treatment (30 weeks), and 15 weeks after calcitriol treatment was stopped (45 weeks) are shown in the seven patients who had responded to calcitriol treatment. The mean basal (pre-dialysis) PTH value is also shown for each study. Mean±SE.
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A wide range of serum PTH, calcium, and phosphate values were available for analysis because parathyroid function was studied before and after calcitriol treatment and 15 weeks after calcitriol treatment was stopped. Shown in Table 4
are the results of covariance analysis performed separately in all eight patients and in the seven responders to calcitriol treatment. The results are presented when as a factor, calcitriol treatment was present (n=8, post-calcitriol treatment) or absent (n=16, combination of pre-calcitriol treatment and 15 weeks after calcitriol was stopped). For the eight patients, basal PTH was affected by changes in ionized calcium and serum phosphate and the effect of calcitriol treatment (P=0.07) approached but did not achieve significance. For maximal PTH, the effect of serum phosphate approached significance (P=0.06) and the effect of calcitriol treatment was significant. Because the effect of serum phosphate did not reach the required P<0.05, stepwise regression was performed with maximal PTH as the dependent variable and the effect of calcitriol treatment was shown to be significant (P=0.001). By covariance analysis, basal/maximal PTH ratio and the set point of calcium were shown to be ionized calcium dependent and calcitriol treatment did not have a significant effect. When only the seven responders to calcitriol treatment were evaluated by covariance analysis, the effect of calcitriol treatment on basal and maximal PTH was significant. Because none of the covariates were significant when basal PTH and maximal PTH were used as response variables, stepwise regression was performed with basal PTH and maximal PTH as dependent variables and showed that the effect of calcitriol treatment was significant for basal PTH (P<0.001) and for maximal PTH (P<0.001). Again covariance analysis showed that the basal/maximal PTH ratio and the set point of calcium were ionized calcium dependent and not affected by calcitriol treatment.
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Table 4. Covariance analysis for response variables, Basal PTH, Maximal PTH, Basal/maximal PTH, and the Set point of calcium in haemodialysis patients treated with calcitriol
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Two methods were used for the calculation of the set point of calcium. The correlation between the set points of calcium (50% and mid-range) was r=0.97, P<0.001.
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Discussion
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In the present study, seven of the eight haemodialysis patients with marked hyperparathyroidism and hypocalcaemia dramatically responded to treatment with intravenous calcitriol. In the patient who failed to respond to calcitriol treatment, hyperphosphataemia was not adequately controlled and hypocalcaemia persisted. Results of covariance analysis suggested that reductions in maximal PTH were calcitriol dependent while reductions in basal PTH were affected by changes in the ionized calcium and serum phosphate. Furthermore, the basal/maximal PTH ratio and the set point of calcium were associated with changes in ionized calcium. Finally, after calcitriol treatment was stopped, serum calcium decreased rapidly, but even after 15 weeks, PTH values remained approximately 50% less than precalcitriol treatment levels.
Apart from the patient who did not respond to calcitriol treatment, all other patients had dramatic reductions of PTH levels during calcitriol treatment. The mean decrease in basal PTH exceeded 90% and was greater than 85% in all seven patients. This marked decrease in basal PTH values was much greater than has been reported in most studies of calcitriol treatment in haemodialysis patients with similar pre-treatment basal PTH levels [5,6,12,15]. In a previous study in haemodialysis patients treated with calcitriol without planned dose reductions [6], only six of 51 (12%) patients had a greater than 80% and 11 of 51 (22%) patients had greater than a 70% reduction in PTH values with treatment. One explanation for the seemingly better response may be that for a similar basal PTH level, the maximal secretory capacity and possibly the parathyroid gland mass is less in hypocalcaemic dialysis patients than in dialysis patients with higher serum calcium levels [7,16].
After calcitriol treatment was stopped, patients were followed for 15 weeks. In the seven patients who responded to calcitriol treatment, the rebound in PTH levels was relatively slow even though hypocalcaemia rapidly developed. Even by 15 weeks, the basal PTH levels remained less than 50% of pre-calcitriol values. Moreover, there was no difference in the rate of rebound in basal PTH levels between patients who before calcitriol treatment had basal PTH levels greater than or less than 1000 pg/ml (data not shown). Only a limited number of studies in dialysis patients have reported the rebound in PTH levels after withdrawal of calcitriol or active vitamin D analogues. In children, patients with the greatest suppression of PTH levels tended to have a more delayed post-treatment rebound [8]. In CAPD patients, PTH levels returned to pre-treatment values within 1 month after calcitriol was stopped [9]. In haemodialysis patients treated with calcitriol for 8 months, PTH rebounded to pre-treatment values 4 months later, but interim values were not reported [10]. In haemodialysis patients treated with 1
-vitamin D2 for 16 weeks, PTH returned to pre-treatment levels by 4 weeks after treatment was stopped [11]. In our study, although hypocalcaemia was present 3 weeks after calcitriol was stopped, the rebound in PTH values was more delayed than in most previous studies. A possible explanation for this difference may be that the magnitude of PTH suppression was considerably greater [911] in our patients and the duration of treatment was longer [8,9,11] than in most previous studies. Also the 3.5 mEq/l calcium dialysate used probably suppressed PTH during every haemodialysis treatment and thus may have played a role.
When all patients treated with calcitriol were evaluated by covariance analysis or if the covariates were not significant, by stepwise regression, both ionized calcium and serum phosphate were associated with changes in basal PTH while only calcitriol treatment was associated with changes in maximal PTH. When only the seven responders to calcitriol treatment were considered, only calcitriol treatment affected the response of basal and maximal PTH. While this latter result is of interest, it perhaps could be considered to be predictable because only patients who responded well to calcitriol treatment were included. A potential criticism of the inclusion of the patient who failed to respond to calcitriol treatment is that the patient was one of the two patients who received the lowest total dose of calcitriol during the 30-week treatment period. While we believe that the failure to control hyperphosphataemia and to correct the hypocalcaemia were major factors in the lack of response to calcitriol treatment, the possibility that the calcitriol dose was inadequate cannot be completely refuted. But it should also be noted that a patient with a similar degree of hyperparathyroidism and who received less than 20 µg more of calcitriol during the 30-week treatment period, had decreases in basal and maximal PTH by 95 and 80% respectively. Finally, irrespective of whether the data were evaluated in all eight patients or only in the seven responders to calcitriol treatment, the basal/maximal PTH ratio and the set point of calcium were ionized calcium dependent. It should also be emphasized that the decrease in the basal/maximal PTH ratio indicates that when maximal PTH is held constant, basal PTH secretion is sensitive to increases in the ionized calcium concentration.
As in previous studies, a close correlation was present between the 50% and mid-range set points of calcium [19,20]. Previous studies have shown that when removed parathyroid glands were studied in vitro, the set point of calcium was greater in glands obtained from patients with greater degrees of hyperparathyroidism [21,22]. However, in the present study, the set point of calcium increased during increases in serum calcium despite calcitriol treatment and reductions in PTH levels. Such results have been shown previously in vivo studies [20,2325] and suggest that the set point of calcium, which is an indicator of the serum calcium concentration at which PTH secretion responds, is influenced by changes in the serum calcium concentration.
In summary, moderate to severe hyperparathyroidism in haemodialysis patients with hypocalcaemia responded well to treatment with calcitriol and a 3.5 mEq/l calcium dialysate. The delayed rebound in PTH levels after calcitriol withdrawal may have been related to the marked PTH suppression during calcitriol treatment and possibly the continued use of the 3.5 mEq/l calcium dialysate. When the data from the three evaluations of parathyroid function were combined, calcitriol treatment was associated with reductions in maximal PTH values while reductions in basal PTH were affected by ionized calcium and serum phosphate. The basal/maximal PTH ratio and the set point of calcium were associated with changes in the ionized calcium concentration. In conclusion, our study showed that (i) moderate to severe hyperparathyroidism in haemodialysis patients with hypocalcaemia responded well to treatment with calcitriol, (ii) reductions in maximal PTH were calcitriol dependent while reductions in basal PTH were affected by changes in the ionized calcium and serum phosphate concentrations, (iii) changes in the basal/maximal PTH ratio and the set point of calcium were calcium dependent, and (iv) the delayed rebound in basal PTH levels after withdrawal of calcitriol treatment may have been due to the long duration of treatment and the marked PTH suppression during treatment.
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Acknowledgments
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The authors gratefully acknowledge that support for this study was provided by a grant from FONDECYT, an agency of the government of Chile. The grant number is 1960785. Results from this study were presented in preliminary form at the 32nd Annual Meeting of the American Society of Nephrology in Miami Beach, FL in November 1999.
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Notes
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Correspondence and offprint requests to: Aquiles Jara MD, Department of Nephrology, Hospital Clinico, Pontificia Universidad Catolica de Chile, Marcoleta 345, Santiago, Chile. 
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Received for publication: 24. 5.00
Revision received 15.12.00.