Different effects of calcitriol and parathytoidectomy on the PTH-calcium curve in dialysis patients with severe hyperparathyroidism

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1 Nephrol Dial Transplant (996) : 8-87 Original Article Nephrology Dialysis Transplantation Different effects of calcitriol and parathytoidectomy on the PTH-calcium curve in dialysis patients with severe hyperparathyroidism F. Malberti, B. Corradi, P. Cosci, M. Colecchia 2, O. Leopardi 2, L. Grossi 3, C. Oldini 3 and E. Imbasciati 'Servizio di Dialisi, 2 Anatomia Patologica and 3 Otorinolaringoiatria, Ospedale Maggiore, Lodi, Italy Abstract Background. The PTH-calcium sigmoidal curve is shifted to the right, the slope of the curve is steeper, and the set point of calcium is increased in dialysis patients with secondary hyperparathyroidism, compared to patients with low-turnover bone disease. These findings could be related to increased parathyroid cell mass and increased sensitivity of parathyroid cells to serum calcium variations in these patients. Calcitriol therapy has been documented to reduce PTH levels by shifting the curve to the left and downward. The effect of a surgical reduction of parathyroid gland mass on the PTH-calcium curve has not yet been investigated. In this study we compared the effects of calcitriol and subtotal parathyroidectomy (PTH) on the dynamics of PTH secretion in response to acute changes of serum calcium in two groups of dialysis patients with severe hyperparathyroidism. Methods. Fourteen dialysis patients treated for 6 months with high-dose i.v. calcitriol ( 2 jag thrice weekly), and dialysis patients who underwent subtotal PTx were studied. The PTH-calcium relationship obtained by inducing hypo- and hypercalcaemia by means of low and high calcium dialysis was evaluated before and 2-6 months after treatment. Results. Both calcitriol and subtotal PTx significantly to serum calcium changes increased with PTx, while on the contrary it decreased with calcitriol. Conclusions. PTH secretion decreases proportionally more with calcitriol than with surgery for a given decrease in the functional mass of parathyroid cells. The change in the PTH-ICa sigmoidal curve induced by subtotal PTx is due to the removal of a large mass of parathyroid tissue with advanced hyperplasia. Key words: secondary hyperparathyroidism; parathyroidectomy; calcitriol; PTH-calcium sigmoidal curve; parathyroid hormone Introduction Several studies have documented that parathyroid hormone (PTH) secretion varies as a function of serum calcium and that the mathematical model which best relates PTH and serum calcium is a sigmoidal curve [-4]. Since ambient serum calcium varies considerably in dialysis patients, basal serum PTH may not always represent the secretory capacity of parathyroid glands, but rather PTH production at a particular serum calcium concentration. As a consequence, dynamic decreased PTH (respectively from 797 ±595 to testing of PTH secretion is needed to better assess and from 36±25 to 7±34pg/ml), as the parathyroid function in uraemic patients. The well as maximal PTH response to hypocalcaemia PTH-calcium curve obtained during hypo- and hyper- (PTHmax), and maximal PTH suppression during -calcaemia has been determined to compare parathyroid hypercalcaemia (PTHmin). When the PTH-calcium function in different forms of renal osteodystrophy curves were constructed using PTHmax as % to [4-6] and to evaluate the effectiveness of different factor for differences in absolute PTH levels and to medical therapies [7-] and dialysis modalities [] provide an assessment of individual parathyroid cell on parathyroid function. function, a shift of the sigmoidal curve to the left and In uraemic patients with osteitis fibrosa, compared downward, and a significant decrease in the set point to patients with low-turnover aluminium-associated of ionized calcium (from to.26±.5 and bone disease or aplastic bone disease without aluminium [4], maximal stimulation of PTH secretion from.36 ±.9 to.22 ±.7 mmol/) was documented with both treatments. However, the slope of induced by hypocalcaemia and the set point of calcium the PTH-calcium curve increased after subtotal PTx are observed at higher serum ionized calcium (ICa) indicating that the sensitivity of the parathyroid cell concentrations, the slope of the PTH-calcium sigmoidal curve is increased, and the sigmoidal curve is Correspondence and offprint requests to: Dr Fabio Malberti, Servizioshifted to the right and upward [4,7]. These findings Dialisi, Ospedale Maggiore, 275, Lodi, Italy. could be related to increased parathyroid cell mass 996 European Dialysis and Transplant Association-European Renal Association

2 82 F. Malberti et al. and increased sensitivity of parathyroid cells to serum calcium variations in these patients. High-dose intravenous or oral calcitriol has been documented to effectively suppresses PTH secretion in dialysis patients with secondary hyperparathyroidism [8-,2-5]. The evaluation of the PTH-calcium sigmoidal curve before and after calcitriol therapy has shown a significant decrease in PTH secretion across a wide range of ICa concentrations [8-,5], a lower maximal PTH secretion induced by hypocalcaemia [8-], and a reduction in the slope of the sigmoidal curve [9]. These findings were in accordance with the well-known suppressive effect of calcitriol on PTH synthesis and secretion [6,7] and were evidence for reduced functional parathyroid gland mass [8-] and reduced sensitivity of parathyroid cells to ICa variations [9,7] after calcitriol therapy. In a previous report [], the sigmoidal curve was studied in a dialysis patient before and after intravenous calcitriol, and after 7/8 parathyroidectomy. Parathyroidectomy (PTx) resulted in a decrease in PTH secretion across a wide range of ICa concentrations and an increase in the slope of the curve. This would indicate that the sensitivity of parathyroid cells increased after PTx. Since one must be cautious in drawing conclusions on findings observed in a single patient, we have undertaken a study to compare the effect of calcitriol and subtotal PTx on the PTHcalcium relationship in a large number of dialysis patients with severe hyperparathyroidism. Subjects and methods The PTH-calcium relationship was investigated in 24 uraemic patients on chronic haemodialysis before and 6 months after intravenous calcitriol (calcitriol group, n= 4) or before and 2-6 months after subtotal PTx (PTx group, n= ). The calcitriol group included 4 of the 9 dialysis patients initially selected for treatment with high-dose i.v. calcitriol because of severe hyperparathyroidism. Eight of the 4 patients were included in a previous study []. The inclusion criteria were PTH levels >3pg/ml, serum ICa within the normal range or only slightly increased ( mmol/), adequate control of hyperphosphataemia (<.7 mmol/, 5.3 mg/dl), histological evidence of osteitis fibrosa with negative aluminium staining. All of the patients were treated with an initial intravenous dose of 2 ug of calcitriol at the end of each dialysis. The duration of the treatment was 6 months. The dose of calcium carbonate or acetate was modified during the study in order to maintain serum phosphate levels below 5.3 mg/dl. Aluminium-containing phosphate binders were not used. Hypercalcaemia (ICa >.35 mmol/) was managed by first reducing the dialysate calcium concentration (from.75 to mmol/) and, if necessary, by also reducing the calcitriol dose (to a minimum of ug twice weekly). The study was interrupted when the patients developed persistent hypercalcaemia (despite the decrease in dialysate calcium and the withdrawal of calcitriol )(n = 4) or hyperphosphataemia (>2 mmol/ )(/i= ). The five patients were considered refractory to calcitriol therapy because they showed an increase in PTH levels during the treatment period. So they underwent PTx, and, thereafter, were included in the PTx group. Thus, only 4 of the 9 initially enrolled patients concluded the study and were considered evaluable. The PTx group included patients with severe hyperparathyroidism and histological evidence of osteitis fibrosa with negative aluminium staining. The indications for PTx were: (a) hyperparathyroidism refractory to high-dose intravenous (5 patients) or oral (3 patients) calcitriol; (b) progressive increase in PTH levels associated with non-compliance or refuse of calcitriol therapy (2 patients). PTx was 7/8 in seven patients, and total with a forearm autograft in three patients. During the surgical operation, a piece of the smallest gland was left in situ or autotransplanted. The histological evaluation of the 4 parathyroid glands removed showed diffuse hyperplasia in 3 glands (excised from 7 patients) and nodular hyperplasia in 27 (excised from 9 patients). As regards the glands left in situ or autotransplanted, the histological pattern of the parathyroid tissue removed was diffuse hyperplasia in seven and nodular hyperplasia in three. After PTx, all of the patients showed PTH levels < 5 pg/ml. The PTH-calcium relationship was evaluated before PTx (at least month after discontinuation of calcitriol) and 2-6 months after PTx. Six of the patients were receiving low-dose oral calcitriol ( ug/day) to maintain normocalcaemia when investigated after PTx. The PTH-ICa relationship was evaluated by inducing hypocalcaemia and, week later, hypercalcaemia in order to maximally stimulate or inhibit PTH secretion by low- and high-calcium haemodialysis (dialysate calciumrespectively and 2 mmol/). PTH and ICa levels were determined at baseline, and after 5, 3, and then every 3min. For the analysis of the PTH-ICa relationship the following terms were used and defined according to Felsenfeld et al. [4]: maximal PTH stimulation (PTHmax) and maximal PTH inhibition (PTHmin) were respectively the highest and the lowest levels of PTH induced by hypo- and hypercalcaemia; the set point of calcium was the ICa value at which PTHmax was reduced by 5%. The PTH-ICa curves were constructed using both absolute PTH values and PTHmax as % to factor for differences in absolute PTH levels between the two periods of the study, and to provide an assessment of individual parathyroid cell function [4]. The sensitivity of parathyroid cells to ICa variations was determined by calculating: (a) the slope of the sigmoidal curve, according to Felsenfeld et al. [4], (b) the slope of the linear regression line between probit PTH and ICa. The probit transformation of the percent PTH was performed to allow linearization and comparison of the curves [8]. From the data obtained by PTH stimulation and inhibition tests, individual PTH-ICa curves and probit PTH-ICa straight lines were constructed for each patient. Composite PTH-ICa curves and probit PTH-ICa straight lines were also constructed for the calcitriol and PTx groups. The PTH and probit PTH values at each ICa level on the composite curves or lines are the mean of the PTH and probit PTH values obtained from each individual curve or line at that particular ICa concentration. The PTH-ICa relationship before and after treatment was compared in the two groups. The sigmoidal PTH-ICa relationship was evaluated by using polynomial regression analysis and the probit PTH-ICa relationship by using linear regression analysis (PSP statistical package), as described elsewhere [,9]. A fourth-degree polynomial equation was used in the polynomial regression analysis to describe the sigmoidal PTH-ICa relationship and obtain the set point of calcium. Successful fits of the individual ICa-PTH data were achieved in each patient using both polynomial regression analysis (r ranging from.93 to.99) and linear regression analysis (r.9-.98; P<.).

3 Effect of calcitriol and parathyroidectomy on the PTH-calcium curve PTH was measured by using a two-site immunoradiometric assay (Nichols Institute, Allegro IRMA PTH kit, normal: -65 pg/ml), and ICa by using a selective ion electrode (ICA2 Radiometer; normal.2-.3 mmol/). The results are reported as means ±SD. Statistical analysis was performed using Student's i test. Results Serum phosphate, alkaline phosphatase and the dose of calcium containing phosphate binders were no different in the calcitriol and PTx groups before treatment (Table ). Serum ICa and PTH levels were slightly, but not significantly higher in the PTx group (Table 2). Taking together the pretreatment PTH secretory parameters of the 24 patients, we found a strong correlation between PTH, and PTHmax (r =.9) and PTHmin (r =.89), as well as between PTHmin and PTHmax (r =.82). Multiple regression analysis (multiple r =.92, P<.) showed that serum ICa (P<.) and PTHmin (P<.2) were the main parameters affecting the set point of calcium, whereas the contribution of the slope, PTH, and PTHmax was not statistically significant. The set point of ICa (x) was positively correlated to ICa (y = x, r =.85), and PTHmin (y = x, r =.57). There was also a signi- ficant correlation between the slope of the sigmoidal curve (x) and the slope of the linear regression line between probit PTH and ICa (y) (y =.3x-.7, r =.67, P<.). Effect of calcitriol After calcitriol alkaline phosphatase significantly decreased from to IU/. In comparison with baseline, the average serum phosphate levels at the end of the treatment period were unchanged (Table ). However, throughout the study, it was necessary to increase the dose of calcium-containing phosphate binders in order to achieve an adequate control of phosphataemia. Phosphataemia was satisfactorily controlled (<2 mmol/) in each patient by using individual doses of g/day of calcium carbonate or acetate as elemental calcium. With the aim of controlling hypercalcaemia, dialysate calcium concentrations were reduced to.5 mmol/ in five patients and to.25 mmol/ in seven patients. Throughout the study the initial calcitriol dose (2 ug thrice weekly) was reduced in all of the patients because of hypercalcaemia. At the end of the treatment period the average calcitriol dose was 2.8 ±.5 ug/week (range 2-4 ug/week). Despite the decrease in dialysate calcium and calcitriol dose, mean serum ICa at the end of the treatment period was significantly higher than at base- Table. Serum phosphate, alkaline phosphatase (ALP), dialysate calcium, and dosage of phosphate binders (as elemental calcium) and calcitriol before and after treatment Serum phosphate (mmol/) ALP (IU/) Ca carbonate/acetate (g/day) Dialysate calcium (mmol/) Calcitriol dose (ug/weelc) Calcitriol.52± ±33.7±.6.7 ±.9 *P<.\ and 2 P<.5 vs baseline; 3 /><. and 4 /><.5 vs calcitriol. After therapy.6 ±.7 236± ±.7' 2.85±.5 Table 2. Effect of calcitriol and subtotal parathyroidectomy (PTx) on PTH secretory parameters Calcitnol After therapy Parathyroidectomy.66 ± ±4 l.9±..7±. Subtotal PTx After PTx 83.5 ±.27 46±3' ±.5.68±. 3.85±.74 3 After PTx ICa (mmol/) PTH (pg/ml) ICa max (mmol/) PTHmax (pg/ml) PTH/PTHmax (%) ICa min 2 (mmol/) PTHmin (pg/ml) PTHmin/max (%) set point ICa (mmol/) slope (%/mmol/l) slope (probit/mmol/).28 ± ±595.3±O.O5 42±935 55±9.43 ± ±299 24±8.3 ± ±39 7. ±2..3± ±244".9± ±538" 38 ± ±.5 86±33 3 8±4".26± ±34" 6. ±.9*.34±.7 36 ±25.8±.6 2±622 52±3.5 ± O±7O 27±2.36 ± ±4 6. ±.8.22± ± ± ± ±4 6 l.36± ± ±9*.22± ±53".± 'ICa max, ICa value at which maximal PTH secretion was observed; 2 ICa min, ICa value at which maximal PTH inhibition was observed. 3 /><. and V<.5 vs baseline; 3 /><. and 6 /><.5 vs calcitriol.

4 84 F. Malberti el al. line (Table 2). Calcitriol therapy significantly lowered PTH, the PTH/PTHmax ratio, maximal PTH response to hypocalcaemia (PTHmax), maximal PTH suppression during hypercalcaemia (PTHmin), the ICa level at which maximal PTH secretion occurred (ICamax), the set point of calcium, the slope of the sigmoidal curve and the slope of the regression line between probit PTH and ICa (Table 2). PTH decreased in each patient after treatment (Figure ). The mean percent decrease was 47 ±23 (range 6-85%). The percentage and the absolute PTH decrease was not different in the five patients with very high baseline PTH levels (>8 pg/ml) compared to those with lower levels (48 ± 23% and 792 ± 65 pg/ml vs 47 ± 25% and pg/ml). The changes in the PTH-calcium curve before and after treatment are shown in Figure 2, in which PTH is reported in absolute values, and in Figure 3, in which PTH is presented as a percent of PTHmax. After treatment, the average before liter Fig.. PTH before and after calcitriol. Mean PTH decreased (P<.5) from 797±595 to 38±244 pg/ml after treatment. PTH, pg/ml 4; ICa mmo/l Fig. 2. Composite plots of individual PTH-ICa sigmoidal curves before (open circles) and after (squares) calcitriol therapy with absolute PTH values. Calcitriol reduced PTH secretion by shifting the curve to the left and downward. PTH levels were significantly lower (P<.2) after calcitriol for each serum ICa level. Closed circles = average baseline levels. % maximal PTH ICa mmol/l Fig. 3. Composite plots of individual PTH-ICa sigmoidal curves before (open circles) and after (squares) calcitriol therapy with maximal PTH secretion transformed to %. Calcitriol reduced PTH secretion by shifting the curve to the left and downward and decreasing the set point of ICa (bars) from.3 ±.5 to.26±.5mmol/l (P<.5). */><.2 between the two periods of the study. Closed circles = average baseline levels. PTH secretion of the 4 patients was significantly lower for each serum ICa level throughout the entire range of serum ICa. This resulted in a shift of the sigmoidal curve to the left and downward (Figure 2 and 3). Effect of parathyroidectomy Subtotal PTx significantly decreased serum ICa, serum PTH, PTHmax, PTHmin, ICa max, ICa min, the set point of ICa (Table 2) and alkaline phosphatase (Table ). Serum phosphate levels and the dose of phosphate binders were not different before and after PTx (Table ). PTH, ICa, PTHmax, PTHmin and ICa min after treatment were significantly lower in the PTx than in the calcitriol group. After subtotal PTx, PTH fell within the normal range in seven patients and remained slightly elevated (between 9 and 5 pg/ml) in three patients. There were no differences in the PTH secretory parameters after PTx between the patients with diffuse or nodular hyperplasia in the remnant parathyroid gland. The composite regression line between ICa and absolute PTH values transformed semilogarithmically to factor for the wide differences in PTH values before and after PTx is reported in Figure 4. Figures 5 and 6 show the composite sigmoidal PTH-calcium curves with PTH values as % and the composite regression lines between probit PTH and ICa in the patients who underwent subtotal PTx. PTx significantly reduced PTH secretion for each ICa level considered. The slope of the sigmoidal curve and the slopes of the regression lines between probit PTH and ICa, and between logpth and ICa increased after subtotal PTx, suggesting that subtotal PTx augments the sensitivity of parathyroid cells to ICa changes (Table 2, Figures 4 and 6). Discussion In the present study we compared the effect of parathyroidectomy and high-dose intravenous calcitriol

5 Effect of calcitriol and parathyroidectomy on the PTH-calcium curve log PTH * - _ # o~'" PTH, pg/ml - a -\ ICa mmol/l Fig. 4. Composite plots of individual PTH-ICa sigmoidal curves before (solid circles, y = 4.44-l.lx) and 2-6 months after (open circles, y = x) subtotal parathyroidectomy (PTx) with absolute PTH values transformed logarithmically to factor for differences in absolute values between the two periods. PTx reduced PTH secretion by shifting the regression line to the left and downward. PTH levels were significantly lower (/»<.) after PTx for each serum ICa level. PTx significantly (P<.) increased the slope of the regression line. % maximal PTH ICa mmol/l Fig. 5. Composite plots of individual PTH-ICa sigmoidal curves before (solid circles) and 2-6 months after (open circles) subtotal parathyroidectomy (PTx). PTx reduced PTH secretion by shifting the curve to the left and downward. PTx decreased the set point of ICa (bars) from.36±.9 to.22±.7 mmol/ (/><.). *P<.\ vs before PTx. PROBIT PTH % maximal PTH Fig. 6. Composite plots of individual probit PTH-ICa linear regression lines before (solid circles, y=3.-6x) and 2-6 months after (open circles, y= 7.3.lx) subtotal parathyroidectomy (PTx). PTH data are given as probit PTH and the percentage of maximal PTH. PTx reduced PTH secretion by shifting the regression line to the left and downward. PTx significantly (/><.) increased the slope of theregressionline. therapy on parathyroid function, as measured by the evaluation of the PTH-calcium curve. The assumption was that differences in parathyroid cell function might result from a lowering of PTH concentrations obtained by a surgical reduction in parathyroid mass or by the calcitriol-induced suppression of PTH synthesis and secretion. Since PTH varies inversely with serum ICa, it might be difficult to determine whether the posttreatment modifications in PTH concentrations are due to a change in serum ICa or the direct effect of treatment on the parathyroid gland. The use of the PTH-calcium curve in clinical studies provides a means by which the independent effects of calcium and therapies, such as calcitriol, on PTH secretion can be separated [8-,7]. Analysis of the PTH values obtained by stimulation and inhibition tests provides relevant information concerning parathyroid function: the maximal PTH level induced by hypocalcaemia (PTHmax) reflects the maximal secretory capacity of the parathyroid gland, the minimal PTH induced by hypercalcaemia (PTHmax) reflects the maximal secretory capacity of the parathyroid gland, the minimal PTH induced by hypercalcaemia (PTHmin) indicates nonsuppressible PTH secretion; the absolute PTH values are considered to be related to the parathyroid gland mass; and the transformation of the absolute PTH values into percentages of maximally stimulated PTH provides an assessment of individual parathyroid cell secretory activity [7]. 85 This study shows that calcitriol suppresses PTH secretion directly by shifting the PTH-calcium curve to the left and reducing the set point of calcium. The decrease in the slope of the sigmoidal curve and in the slope of the regression line between probit PTH and ICa indicates that the sensitivity of the parathyroid cell to calcium changes was reduced by calcitriol. Similar results were reported in a previous study []. Dunlay et al. [8] documented in nine dialysis patients with hyperparathyroidism a reduction in basal, maximal and minimal PTH levels after weeks of highdose i.v. calcitriol; six of the nine patients, who continued to receive calcitriol, showed, after 42 weeks of therapy, a further decrease in PTH levels for a similar calcium concentration and a significant reduction of the slope of the sigmoidal curve, without any modification in the set point of calcium [9]. Thus it is likely that the modifications in the PTH-calcium curve induced by calcitriol depend on the dose and duration of treatment and the responsiveness to calcitriol of the individual patient. In our patients, calcitriol therapy markedly decreased maximal PTH secretion induced by hypocalcaemia, the ICa level at which maximal PTH secretion occurred, and both the absolute and percentage basal and minimal PTH levels. This resulted in the shift of the sigmoidal curve to the left, in the decrease in the set point of calcium and in the slope of the curve. These findings indicate that calcitriol lowers PTH secretion by decreasing PTH production per cell, and are in accordance with the extensively demonstrated suppressive effect of calcitriol on PTH synthesis and secretion [6]. Another possible median-

6 86 ism by which calcitriol could lower PTH levels is the decrease in parathyroid cell number. Fukagawa et al. [4,2] documented by ultrasonography a decrease in parathyroid gland size after high-dose oral calcitriol, and apoptosis of the parathyroid cells has been proposed as the possible mechanism. However, the regression of parathyroid gland mass was observed in patients with mild hyperparathyroidism showing smallsize parathyroid glands [2]. On the contrary, Quarles et al. [2] did not find any significant change in parathyroid gland size after high-dose intravenous calcitriol in 9 dialysis patients with severe hyperparathyroidism. Unfortunately we did not measure the parathyroid gland mass before and after calcitriol, so the effect of calcitriol on regression of parathyroid hyperplasia is not supported by our study. However, the evaluation of maximal PTH stimulation suggests that the functional parathyroid gland mass has been reduced in our patients by calcitriol. This is in agreement with the results of a recent study, which has documented by means of thallium-technetium subtraction scintigraphy that the decrease in PTH after longterm intravenous calcitriol was associated with a reduction in thallium uptake [22]. The group of patients who underwent subtotal PTx showed a degree of secondary hyperparathyroidism as severe as the patients treated with calcitriol, since pretreatment levels of ICa, PTH and alkaline phosphatase were comparable in the two groups. The absolute levels of PTH, PTHmax and PTHmin markedly decreased after subtotal PTx, in keeping with the surgical removal of most of the parathyroid gland mass. When the PTH-ICa curves were constructed using PTHmax as % to factor for differences in absolute PTH levels between the two periods of the study, a shift of the sigmoidal curve toward the left and downward, and a significant decrease in the set point of ICa was documented. Furthermore, subtotal PTx not only reduced PTH secretion at any ICa level, but also increased the slope of the PTH-ICa curve, thus indicating that the sensitivity of the parathyroid cell to ICa changes increased. With subtotal PTx, we completely removed the three largest parathyroid glands, maintaining in situ or autoimplanting a piece of the smallest gland. The histological pattern of the parathyroid tissue of the glands left in situ or autotransplanted showed diffuse hyperplasia in seven cases and nodular hyperplasia in three, while 24 of the 3 glands removed showed nodular hyperplasia. Nodular hyperplasia is considered a more advanced stage of parathyroid hyperplasia than diffuse hyperplasia because it is associated with abnormal PTH secretion and more aggressive cell proliferation [23]. Moreover, the control of PTH release by calcium has been documented to be abnormal in the parathyroid cells obtained from nodules [24]. Thus, the shift of the sigmoidal curve to the left and downward and the increase in the slope observed after PTx could be the result of both the drastic reduction in parathyroid cell numbers and the removal of parathyroid tissue with advanced histological lesions. On the other F. Malberti et al. hand, the sigmoidal PTH-calcium curve was shown to be shifted to the left and the set point of calcium to be decreased in dialysis patients with mild hyperparathyroidism compared to those with a more severe hyperparathyroidism []. There is emerging evidence that phosphate may exert a direct effect on the parathyroid glands [25]. The reduction in serum phosphate levels after lowphosphate low-protein diets has been documented to decrease both minimal and maximal PTH levels and to shift the sigmoidal curve downward, without modifying the slope of the curve and the set point of calcium [25]. Serum phosphate did not change significantly in the calcitriol and PTx groups during the study, nor serum phosphate levels were different between the two groups. Thus the variations in the PTH response to ICa changes after PTx or calcitriol treatment were not related to phosphate changes in our patients. Preliminary results have suggested that the set point of calcium may adapt to the ambient calcium, since, despite calcitriol treatment, the increase in predialysis serum calcium was associated with an increase in the set point of calcium, while the decrease in calcaemia after the discontinuation of calcitriol, resulted in a reduction of the set point [26]. In our study, calcitriol treatment shifted the PTH-calcium curve to the left and decreased the set point of calcium, despite a significant increase in basal serum ICa. However, the shift of the set point of calcium to the left after PTx was associated to the reduction in basal serum ICa levels. Thus, we cannot exclude that the decrease of the set point after PTx in our patients may partially be due to an adaptation of the parathyroids to the lower ambient calcium levels. In conclusion, our study shows that substantial differences in parathyroid cell function can be brought about by lowering PTH levels by means of calcitriol therapy or the surgical reduction of parathyroid mass (subtotal PTx). Although both have been shown to effectively decrease PTH levels by shifting the PTH- ICa curve to the left and downward, the sensitivity of parathyroid cells to ICa variations increased after PTx, whereas it decreased with calcitriol. These findings suggest that the secretion of PTH decreases proportionally more with calcitriol than with surgery for a given decrease in the functional mass of parathyroid cells. The changes in the PTH-ICa sigmoidal curve after subtotal PTx are likely to be due to the removal of parathyroid tissue with advanced histological lesions, besides the drastic reduction in parathyroid cell mass. References. Mayer GP, Hurst JG. Sigmoidal relationship between parathyroid hormone secretion rate and plasma calcium concentrations in calves. Endocrinology 978; 2: Brown EM. Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 983; 56: Brent GA, LeBoff MS, Seely EW, Conlin PR, Brown EM. Relationship between the concentration and rate of change of

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