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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 11 3839-3844
Copyright © 1998 by The Endocrine Society

Original Studies

The Set Point of Parathyroid Hormone Stimulation by Calcium Is Normal in Progressive Renal Failure

H. Cardinal, J.-H. Brossard, L. Roy, R. Lepage, L. Rousseau and P. D’Amour

Centre Hospitalier de l’ Université de Montréal Research Center, Saint-Luc Campus, and Departments of Medicine and Biochemistry, University of Montreal, Montreal, Quebec H2X 1P1, Canada

Address all correspondence and requests for reprints to: Pierre D’Amour, M.D., Centre de recherche du Centre Hospitalier de l’ Université de Montréal, Campus Saint-Luc, 264 René Lévesque Boulevard East, Montreal, Quebec H2X 1P1, Canada.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
An increased set point of PTH stimulation by ionized calcium (Ca++) has been observed in renal failure patients with severe secondary hyperparathyroidism. The extension of this concept to all renal failure patients has remained problematic, even if it could explain elevated PTH levels in the absence of other biochemical abnormalities. We were particularly interested in seeing whether the concept could fit patients with progressive renal failure (PRF). To achieve this, we studied 26 normals (N), 9 patients with PRF, and 12 hemodialyzed patients (HD) in the basal state and during parathyroid function tests. The latter two groups were studied at the end of winter and end of summer, respectively. Patients with PRF had normal levels of Ca++, PO4, and 1,25(OH)2D, and they had low-normal concentrations of 25(OH)D; their basal I- and C-PTH levels were 3- and 4-fold higher than N, as were their creatinine levels. HD had significantly lower levels of Ca++ and 1,25(OH)2D, and they had higher levels of phosphate, creatinine, I-PTH, and C-PTH than N or PRF. Stimulated levels of I-PTH were similar in N (13.6 ± 4.3 pmol/L) and PFR (18 ± 3.3 pmol/L) and elevated in HD (37.1 ± 28.7 pmol/L; P < 0.001 vs. N, and P < 0.05 vs. PRF). Nonsuppressible I-PTH was increased 2-fold in PRF (N = 0.64 ± 0.19 vs. PRF = 1.28 ± 0.46 pmol/L; P < 0.01) and 6-fold in HD (3.95 ± 2.85 pmol/L; P < 0.001 vs. others). But the set point of I-PTH stimulation by Ca++ was normal in PRF (N = 1.18 ± 0.03 vs. PRF = 1.20 ± 0.04 mmol/L; not significant) and decreased in HD (1.09 ± 0.04 mmol/L; P < 0.001 vs. others). Similar results were obtained with the set point of C-PTH and of the C-PTH/I-PTH ratio. A positive correlation was observed between serum Ca++ concentration and the set point value when all three populations were analyzed together (r = 0.759, n = 47, P < 0.0001). These results indicate that the set point of PTH stimulation is normal in PRF and decreased in hypocalcemic HD. The set point seems to adjust to the ambient Ca++ concentration of the patients, by mechanisms yet to be elucidated. This does not suggest participation of this factor to the genesis of the secondary hyperparathyroidism of PRF.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ROLE of the set point of PTH stimulation by ionized calcium (Ca++) in the genesis of secondary hyperparathyroidism in renal failure remains unclear. Elevation of the set point value was observed on parathyroid cells obtained from glands of renal failure patients with tertiary hyperparathyroidism (1). The application of these data to all renal failure patients remains problematic, because they may reflect tertiary hyperparathyroidism rather than renal failure. Data obtained in normals (N) (2, 3) and in hemodialyzed patients (HD), during a study of their parathyroid function, suggest that the latter individuals have either a normal or a low set point (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17), and a relationship between the set point value and the Ca++ concentration has been described in these patients (16, 17). These data suggest that the set point of PTH stimulation by Ca++ is only increased in a minority of patients with advanced renal failure and severe secondary hyperparathyroidism (18). The subject is less clear in early renal failure. Factors classically involved in the genesis of the secondary hyperparathyroidism, low levels of Ca++ and 1,25(OH)2D and elevated phosphate concentrations, are usually seen when PTH is already clearly elevated (19). An increased set point of PTH stimulation by Ca++ could, at this stage of renal failure, increase PTH concentration without any other requirements. A single study (20), so far, suggests that this may not be the case. The present study was thus planned to see whether an increase in the set point of PTH concentration by Ca++ could contribute to increased PTH levels observed in progressive renal failure (PRF), before other biochemical changes that are likely to increase PTH concentration.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Twenty-six normal individuals, who had participated in parathyroid function and I-PTH high-performance liquid chromatography composition studies (2, 21), served as controls. Twelve HD, who also participated in similar studies (16), were used as examples of end-stage renal failure. Thirty patients, followed at the nephrology clinic of our medical center, had their creatinine clearance measured to study the influence of their renal function on the accumulation of non-(1–84) human PTH (hPTH), detected by intact PTH assays (22). Patients with creatinine clearance between 10 and 90 mL/1.73 m2·min, who had never had dialysis as part of their treatment, were then invited to participate in a study of their parathyroid function, making sure that the overall range of renal function was covered. Nine patients agreed to participate in the study, covering a creatinine clearance range of 14.5–87 mL/1.73 m2·min.

Experimental protocol

The protocol was approved by a local ethics committee. All participants signed an informed consent form. All subjects were studied while maintaining their usual diet. Patients with PRF were studied in May (at the end of winter). HD were studied in October (at the end of summer). Blood was obtained from all subjects after an overnight fast, where water was permitted. A 24-h urinary specimen was also obtained from patients with PRF, to measure creatinine clearance.

An evaluation of parathyroid function was carried out in all subjects. Different protocols were used to increase and decrease Ca++ concentration in the three populations. The goals were to increase Ca++ concentration by 0.3 mmol/L or more (or above 1.5 mmol/L) in a first session and to decrease it by 0.2 mmol/L or more (or near a final concentration of 1.0 mmol/L) in a second session. In normal subjects, CaCl2 and Na2EDTA infusions were performed as previously described (2, 21). On the first occasion, serum Ca++ was increased over 90–120 min by means of an iv infusion of CaCl2 in 50 g/L dextrose, which provided 125 µmol elemental Ca/kg·h. The rate of the infusion increased progressively, to approximately twice the initial rate at the end. Four to 7 days later, serum Ca++ was decreased by means of an iv infusion of Na2EDTA, which provided 51 µmol/kg·h over 2 h. The rate of the infusion increased progressively, as it had done for the CaCl2 infusion. Procaine HCl (12.5 µmol/kg·h) was added to the Na2EDTA solution to relieve arm pain during the infusion. In PRF patients, CaCl2 and Na citrate infusions were performed. The first infusion was similar to that for normal individuals. Na citrate (255 µmol/kg·h over 2-h) was used to decrease Ca++ concentration, because Na2EDTA had become unavailable to us. The rate was increased progressively, to reach twice the initial rate at the end of infusion. Procaine HCl was added to the Na citrate to relieve arm pain, as in N. In HD, Ca++ concentration was first increased, and then decreased 1 week later by modulating Ca++ dialysate concentration over 2–3 h, as previously described (16). Ca++ was first increased using Ca++ dialysate concentrations of 1.5, 1.75, and 2 mmol/L for 30, 30, and 60–90 min, respectively. One week later, Ca++ was decreased using Ca++ dialysate concentrations of 1.0, 0.75, and 0.5 mmol/L for 30, 30, and 60–90 min, respectively. In all three protocols, blood samples were obtained before initiating Ca++ modulation, and every 15 min thereafter, to measure Ca++, I-PTH, and C-PTH.

Laboratory methods

Ionized calcium was measured, immediately after blood collection, with a ICA2 ionized calcium analyzer (Radiometer, Copenhagen, Denmark); the interassay coefficients of variation for 38 determinations at concentrations of 0.77 and 1.75 mmol/L were 3.3% and 2.7%, respectively. Serum phosphate, creatinine, and alkaline phosphatase were measured by automated colorimetry. Serum 25-hydroxyvitamin D and 1,25(OH)2D were measured after extraction with acetonitrile. 1,25(OH)2D was further chromatographed on C-18 and silica cartridges before measurement by a commercial assay (INCSTAR Corp., Stillwater, MN). The within-assay coefficient of variation for duplicate determinations was 6% for 25(OH)D assay and 10–14% for 1,25(OH)2D assay. Serum PTH was measured by means of 2 different PTH assays. The first was a commercial immunoradiometric assay for intact hPTH(1–84) (Allegro Intact PTH, Nichols Institute Diagnostics, San Juan Capistrano, CA). This assay was initially reported to react only with hPTH(1–84), because synthetic hPTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) was not retained by the carboxylterminal-directed solid-phase antibody, and synthetic hPTH(39–84) and (39–68) were not recognized by the labeled aminoterminal-revealing antibody (23, 24). Nonetheless, this and other commercial I-PTH assays (25) have been demonstrated to react with a molecular form of PTH other than hPTH(1–84) in man when sera obtained under various calcemic conditions were fractionated by high-performance liquid chromatography (21, 26). The reported detection limit of the assay is 0.1 pmol/L in the company’s brochure. The intraassay coefficient of variation for duplicates is 3.1%. Serum C-PTH was measured by an in-house C-PTH assay, described previously (2). This assay detects predominantly large carboxylterminal fragments, hPTH(1–84) being 4–6 times less reactive on a molar basis than hPTH(39–84) and hPTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34), and hPTH(39–68) or (44–68) being nonreactive (2). The antigenic determinant is in the region (65–84) of the PTH molecule. The detection limit was calculated at 1 pmol/L, using 3 SD from standard 0 run in quadruplicate, in 10 different assays. The intraassay coefficient of variation at 50% binding is 3.3%. For PTH measurements, all patients with PRF were measured in the same assay.

Mathematical and statistical analysis

Results are presented as means ± SD. Within-group comparisons were performed by a paired Student’s t test. Comparisons between groups were performed by a one-way ANOVA, followed by Student-Newman-Keuls comparison test for two x two comparisons. A standard method was used for simple regression. The parathyroid function of each individual was analyzed using a mathematical model fitting the sigmoidal relationship between I- or C-PTH and Ca++ concentrations, as previously described by us and others (2, 21, 27). A minimum of 15 points, derived from the hypocalcemic and hypercalcemic infusions, was used for each analysis. The fitting of the calculated curve to the experimental points was evaluated via the square of the correlation coefficient (R2). The C-PTH/I-PTH ratio was also analyzed, as a function of Ca++ concentration, using the same mathematical model, because this relationship also fits a sigmoidal function. This analysis enables the monitoring of relative changes in circulating molecular forms of PTH, as a function of serum Ca++ concentration (2). Raw data were analyzed using the Origin nonlinear sigmoid curve fit module (Microcal Software Inc., North Hampton, MA).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go illustrates the characteristics of the three groups studied. Normal individuals tended to be younger than renal failure patients. Patients with PRF had a mean creatinine value that was between that of normal individuals and HD. Their creatinine clearance ranged from 14.5–87 mL/1.73 m2·min, four patients having values above 50 mL/1.73 m2·min (50.7, 54.2, 65.5, and 87) and five having values below (43.6, 41.6, 34.2, 21, and 14.5). Patients with PRF also differed from normal individuals by having higher I- and C-PTH levels and a higher C-PTH/I-PTH ratio, while having similar Ca++ and phosphate values and a 1,25(OH)2D level in the normal range. Their mean 25(OH)D level was at the lower limit of normal at the end of winter, and four patients had values below the lower limit of normal. HD were hypocalcemic, hyperphosphatemic, and had low levels of 1,25(OH)2D. Their mean 25(OH)D concentration was higher at the end of summer. They also showed a more marked degree of secondary hyperparathyroidism than patients with PRF.


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  		Table 1. Characteristics of the three groups

 
Because different protocols were used in the three groups, to modulate Ca++ concentration, we had first to make sure that sufficient stimuli were achieved in the three groups. This analysis is summarized in Table 2Go. The time required to induce hypercalcemia, the degree of hypercalcemia, and the {Delta}calcium concentration were similar in N and PRF patients. HD, on the other hand, started with a lower initial calcium concentration, achieved the expected goal of 0.3 mmol/L or more, but remained with a significantly lower {Delta}Ca++ increase, even if stimulated for a longer time period. The hypocalcemic level achieved was significantly lower in PRF and HD, compared with N, but the mean lowest Ca++ concentration was near or below the 1 mmol/L goal in all groups. Even with these differences, maximum stimulation and inhibition of PTH was achieved in all subjects. A representative individual from each group is illustrated in Fig. 1Go, with all experimental points, to show how fitting of the sigmoid function curve was achieved. As illustrated with these three patients, maximum inhibition was always present at a Ca++ concentration of 1.3 mmol/L or more; and similarly, maximum stimulation was generally achieved at a Ca++ concentration of 1.05–1.10 mmol/L, the only exceptions being HD with severe secondary hyperparathyroidism (Fig. 1Go bottom), who required Ca++ concentrations less than 1.0 mmol/L to achieve maximum stimulation.


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  		Table 2. Comparison of parathyroid function protocols in the three groups

 


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  		Figure 1. The parathyroid function, measured with the I-PTH assay, is shown for a representative patient in each group, to illustrate the fitting of the sigmoid curve to the raw data. Normal individual, top; PRF, middle; HD, bottom. MAX, Maximum; MIN, minimum; SP, set point.

 
Table 3Go illustrates the results of the parathyroid function in the same groups. With the I-PTH assay, the maximum response to hypocalcemia was only increased in HD, but the range of values varied from normal (11.2 and 11.7 pmol/L) to greatly elevated (62, 71, 73, and 90 pmol/L). The sensitivity to Ca++ changes (slope) was increased in patients with PRF and decreased in HD. The set point of PTH stimulation by Ca++ was similar in N (range, 1.1–1.22 mmol/L) and in patients with PRF (range, 1.14–1.26 mmol/L) and decreased in HD (range, 1.03–1.16 mmol/L). The nonsuppressible fraction of I-PTH was increased in all renal failure patients, but more so in HD. If we except the maximum response of C-PTH to hypocalcemia, which was also increased in PRF (compared with normal), changes in set point and in the nonsuppressible fraction of C-PTH were similar to those previously described for I-PTH. Finally, the C-PTH/I-PTH ratio value in hypocalcemia and hypercalcemia were increased in renal failure patients, compared with N, and more so in HD. The set point of this ratio also disclosed the same characteristics as those described for the I- and C-PTH set point in the three groups. These results are also illustrated for I-PTH on Fig. 2Go. The mean parathyroid function of each group is shown either in absolute value (left) or as a percentage of the maximum (right), to demonstrate set point differences. Only HD show a lower set point.


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  		Table 3. Analysis of parathyroid function in the three groups

 


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  		Figure 2. The mean parathyroid function, obtained with an intact PTH assay in normal individuals (solid line), in patients with PRF (···), and in HD (·- ·- ), is illustrated on the left in absolute values (pmol/L) and on the right as a percent of maximum to outline set point differences. HD have a significantly lower set point, compared with the other two groups (P < 0.001). Similar results were obtained with the set point using a C-PTH assay or the C-PTH/I-PTH ratio (not illustrated).

 
Figure 3Go illustrates the relationship between serum Ca++ concentration and the set point of I-PTH stimulation by calcium for the three groups analyzed together. A significant positive relationship is observed between these two parameters (r = 0.759, n = 47, P < 0.0001) when all groups are analyzed together or when N are analyzed with PRF patients or when all renal failure patients are analyzed together (data not shown).



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  		Figure 3. Relationship between Ca++ concentration and the set point of I-PTH stimulation by Ca++, in all 47 subjects studied in the present and previous studies (2 16 26 ). The correlation was present when the three groups were analyzed together or when patients with PRF ({blacksquare}) were analyzed with normal individuals (•) or with HD ({blacktriangleup}) (data not shown).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study was performed to see whether an increased set point of PTH stimulation by Ca++ could be implicated in the secondary hyperparathyroidism of PRF, before or with other biochemical abnormalities likely to increase circulating PTH concentration. Low Ca++ and high phosphate levels are generally seen when the glomerular filtration rate is below 30 mL/1.73 m2·min (19, 28). Lower levels of 1,25(OH)2D, still within the normal range, have been described with a glomerular filtration rate of 60 mL/1.73 m2·min (19, 28, 29, 30, 31). In our patients with PRF, creatinine clearances ranged from 14–87.5 mL/1.73 m2·min, Ca++ and phosphate values were comparable with N, 1,25(OH)2D values were in the low-normal range, and 25(OH)D values were low normal at the end of winter, whereas I- and C-PTH values were clearly elevated. Because four patients had decreased 25(OH)D values in that group, we cannot exclude the possibility that this factor plays a part in their PTH levels, as demonstrated in other conditions (32). These results are similar to those described by others in patients with similar renal function (19, 28, 29, 30, 31).

The parathyroid function of our patients with PRF was the main focus of this paper. There were differences among the groups, related to the different protocols used to study the parathyroid function. More time was required to achieve hypercalcemia in HD, and their {Delta}Ca++ increase was significantly less than in the other two groups. But the goal of increasing the initial Ca++ concentration by at least 0.3 mmol/L was achieved in all cases. A clear plateau of suppressed PTH values was also achieved in all cases. Maximum suppressibility was present at a Ca++ concentration of 1.3 mmol/L in all individuals, a Ca++ value well below the mean final Ca++ concentration achieved in each group. More time was also required to achieve hypocalcemia in HD. The degree of hypocalcemia achieved was more marked in HD and those with PRF. In addition, the {Delta}Ca decrease was sufficient to achieve a plateau in all individuals, maximum stimulation usually being already achieved at a Ca++ concentration of 1.05–1.1 mmol/L. The only exceptions were HD with greatly increased parathyroid function and a low set point; and, in this group, the mean Ca++ concentration was decreased to 0.95 ± 0.02 mmol/L. In this last group, the rate of calcium change was also slower during both infusions, but this factor has been shown not to influence the final results of the parathyroid function when the Ca++ concentration is kept moving over the entire time course of both infusions, as was the case here (33, 34).

PRF patients had a stimulated I-PTH value similar to N, while having a significantly higher nonsuppressible fraction, a greater sensitivity to calcium, and a normal set point of I-PTH stimulation by calcium. These results in our patients are similar to those obtained by Messa et al. (20) in patients with a GFR of approximately 45 mL/1.73 m2·min. Even when the parathyroid function was studied with a carboxylterminal assay, disclosing elevated stimulated and nonsuppressible C-PTH values compared with N, the mean value of the set point of C-PTH stimulation by Ca++ remained similar to N. The modulation of the C-PTH/I-PTH ratio by calcium also disclosed a set point value similar to N, even though the values of this ratio in hypo- and hypercalcemia were significantly elevated, compared with N. This demonstrates that the set point of PTH stimulation by calcium is normal in PRF. This was not the case in many of our HD, who disclosed increased values of stimulated and nonsuppressible I- and C-PTH, compared with the other two groups, and decreased values of I- or C-PTH stimulation set point. This is similar to results obtained by various studies (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17) in HD.

A few studies have demonstrated that the set point of I-PTH stimulation by calcium is related to the serum calcium concentration of same patients (16, 17). We have described a similar relationship between the mean serum concentration of calcium and the mean set point of I-PTH stimulation by calcium, when all published studies on the parathyroid function of renal failure patients are analyzed together (16). In the present study, we are again able to demonstrate a relationship between serum calcium concentration and the set point of I- or C-PTH (not illustrated) stimulation by calcium, when all groups are analyzed together or when PRF patients are analyzed with N or with HD alone (not shown). Part of the relationship between serum calcium concentration and the set point of PTH stimulation by calcium may be methodological. Hypocalcemic patients sit higher on their parathyroid function curve in the basal state, and more experimental points are obtained while raising calcium concentration. This will shift their parathyroid function curve to the left (lower set point) in relation with the hysteresis phenomenon in PTH secretion, as previously analyzed by us (16) and demonstrated by others (35). It remains that, in previous study, part of the relationship is still secondary to an adjustment of the set point to the ambient calcium concentration by mechanisms yet to be identified (16).

In conclusion, the set point of PTH stimulation by calcium is not involved in the increased PTH levels observed in PRF. The increased set point of PTH stimulation observed in patients with tertiary hyperparathyroidism (1, 18) is most likely a reflection of their tertiary hyperparathyroidism, rather than their renal failure. In advanced renal failure, the set point of PTH stimulation by calcium seems to follow the evolution of serum calcium concentration. Further studies will be required to see how this is accomplished.

Received June 8, 1998.

Revised July 23, 1998.

Accepted July 31, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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