The set point of calcium and the reduction of parathyroid hormone in hemodialysis patients

Kidney International, Vol. 49 (1996), pp. 226—231

The set point of calcium and the reduction of parathyroid hormone in hemodialysis patients MADELAINE PAHL, AQUILES JARA,' JORDI BOVER,2 MARIANO RODRIGUEZ, and ARNOLD J. FELSENFELD Departments of Medicine, West Los Angeles VA Medical Center, UCLA, and UC Irvine, Los Angeles and Irvine, California, USA, and the Unit of Investigation, hospital Reina Sofia, Cordoba, Spain

The set point of calcium and the reduction of parathyroid hormone in hemodialysis patients. Since in some studies in hemodialysis patients

calcitriol treatment has resulted in a reduction of both parathyroid hormone (PTH) levels and the set point of calcium, it has been suggested

that the set point of calcium reflects a reduction in the magnitude of hyperparathyroidism. However, others have maintained that the set point of calcium is primarily an indicator of the serum calcium at which PTH is secreted and may be dissociated from the magnitude of hyperparathyroidism. The present study was designed to evaluate how a reduction in PTH levels associated with an increase in the predialysis (basal) serum calcium would affect the set point of calcium. Two different treatments were used

to produce a reduction in PTH that was associated with an increase in predialysis serum calcium. In the first group, hemodialysis patients received 2 rg of intravenous calcitriol and were dialyzed with a 3.5 mEq/liter calcium dialysate for six weeks; in the second group, hemodialysis patients were dialyzed with a 4 mEq/liter calcium dialysate and had oral calcium

supplementation increased for six weeks. In both groups, low and high calcium studies were performed to determine the PTH-calcium relationship before treatment, at the end of six weeks of treatment, and six weeks after the discontinuation of treatment. In the calcitriol group, the predialysis calcium increased from 9.62 0.34 to 10.56 0.31 mgldl, P < 0.05 and the Set point of calcium increased from 9.34 0.23 to 9.79 0.25 mgldl, P < 0.05 at the same time as maximally stimulated PTH decreased from 2637 687 to 1555 617 pg/mI, P < 0.05. In the high calcium 0.31 dialysate group, the predialysis serum calcium increased from 9.19 to 9.84 0.28 mg/dl, P < 0.05, and set point of calcium increased from 9.01 0.28 to 9.39 0.22 mg/dl, P < 0.05 at the same time as maximally stimulated PTH decreased from 1642 450 to 1349 513 pg/mI, P <

Discontinuation of treatment for six weeks resulted in a return to pretreatment values. In conclusion, our results would suggest that (1) the Set point of calcium may not be a reliable indicator of the magnitude of hyperparathyroidism during calcitriol treatment, and (2) PTH secretion may adapt to the ambient serum calcium concentration. 0.05.

In most studies in hemodialysis patients, calcitriol treatment has

resulted in a reduction in parathyroid hormone (PTH) levels [1—41. However, while ealcitriol treatment of dialysis patients with

secondary hyperparathyroidism has been shown to reduce PTH levels, the effect of calcitriol on the set point of calcium, defined

as the serum calcium concentration at which maximal PTH secretion is reduced by 50% [5], is controversial inasmuch as some studies have reported a reduction in the set point of calcium [3, 6, 7], while in other studies, the set point of calcium did not change

despite a reduction in PTH levels [2, 4, 8, 9]. Moreover, it has been suggested that the set point of calcium reflects the reduction in the magnitude of hyperparathyroidism, and thus an inability to

reduce the set point of calcium indicates a refractoriness to treatment that may require a parathyroidectomy [3, 7, 91. The concept that the set point of calcium may be related to the mass of the parathyroid glands was first suggested as a result of a series of in vitro studies by Brown et al [10, 11] and a study in neonatal calves by Keaton et al [12]. As a result of these studies, the concept was generated that the set point of calcium may be an

indicator of parathyroid gland mass, or in clinical terms, the magnitude of hyperparathyroidism. However, in vivo, PTH secre-

tion is not only dependent on the serum calcium concentration, but also the serum calcium concentration is a function of the effect

of PTH on target organs such as kidney and bone. Moreover, a dissociation between the set point of calcium and the magnitude of hyperparathyroidism may become particularly apparent in the setting of renal failure in which skeletal resistance to the calcemic

action of PTH [13], an inability to modulate renal calcium excretion [14], a calcitriol deficiency [15], and hyperphosphatemia [13] are generally present. Previous studies have shown that the serum calcium concentration is tightly regulated in the normal human [16]. However, the serum calcium concentration varies considerably among dialysis

patients. In a recent study in hemodialysis patients, we have observed that the range of serum calcium between maximal and minimal PTH was constant although the basal serum calcium was different [17]. In another study in which the PTH response to hypocalcemia was evaluated in hemodialysis patients with a broad range of predialysis serum calcium, PTH secretion also appeared to vary according to the ambient serum calcium [18]. Such findings

Current Address: Hospital Clinico, Pontificia Universidad Catolica de Chile, Santiago, Chile; 2 Current Address: Hospital de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain Received for publication March 19, 1995 and in revised form July 25, 1995 Accepted for publication July 27, 1995

© 1996 by the International Society of Nephrology

resulted in our questioning whether PTH secretion in the dialysis patient may adapt to the ambient serum calcium.

The goal of the present study was to evaluate in a group of hemodialysis patients with basal PTH levels > 250 pg/mI, the effect that intentionally increasing the serum calcium by two different methods had on the set point of calcium and PTH secretion. Serum calcium was increased either by treatment with (I) calcitriol and a high normal dialysate calcium concentration

226

Pahi et al. Set point of calcium and PTH

(3.5 mEq/liter) or (2) an increased calcium dialysate concentration (4 mEqlliter) and supplemental oral calcium.

227

hypocalcemia and which an additional reduction of the serum calcium did not further increase the PTH value; (3) minimal PTH

(PTHmin) was the lowest PTH level during suppression by

Methods hypercalcemia and which a further increase in the serum calcium Eleven maintenance hemodialysis patients were studied. All did not result in any additional decrease in PTH; (4) the ratio of patients had predialysis intact PTH levels greater than 250 pg/mI basal to maximal PTH (Basal/Max PTH) was the basal PTH at the start of the study. Before the start of the study, patients divided by the maximal PTH and this fraction was multiplied by were dialyzed for 3.5 to four hours thrice weekly with a dialysate 100 to provide a percentage; in normal volunteers, this ratio is 20 calcium concentration that ranged from 2.5 to 3.5 mEq/liter. Their to 25% [20]; (5) the ratio of minimal to maximal PTH (Mm/Max mean age at the time of study was 49.4 4.6 years (range 24 to 72 PTH) was the minimal PTH divided by the maximal PTH and this years) and the mean duration of dialysis was 59.8 11.6 months fraction was multiplied by 100 to provide a percentage; in normal (range 7 to 136 months). Six patients were male and five were volunteers, this ratio is 3 to 5% [201; (6) the set point of calcium female. All patients used calcium carbonate as their primary was defined as we have done previously [2, 4, 17, 19] as the serum phosphate binder. None of the patients had received any calcitriol calcium concentration at which maximal PTH secretion was or other forms of vitamin D for at least six weeks prior to study. reduced by 50%; (7) the basal serum calcium was the serum Studies were performed at the hemodialysis units of the Univer- calcium concentration at the basal (predialysis) PTH; (8) the sit)' of California at Irvine and the West Los Angeles VA Medical serum calcium at maximal PTH (Cam) was the serum calcium Center. The protocol was approved by the appropriate committee concentration at which the PTH level was first observed to be for human studies at both institutions and all patients gave maximal or within 10% of the maximal PTH; this definition was used because the PTH-calcium curve is sigmoidal and as the PTH informed consent. As described in our previous studies [2, 4, 17—19], the PTH value approaches the asymptotic portion of the curve, considerresponse to hypo- and hypercalcemia was evaluated. Briefly, a low able variation in serum calcium can be observed during small

calcium hemodialysis (1 mEq/liter) was performed to induce changes in PTH; similarly, for the same reason, (9) the serum calcium at minimal PTH (Camin) was the serum calcium concentration at which the PTH level was first observed to be minimal or within 10% of the minimal PTH. Intact PTH was measured with an immunoradiometric assay for obtained at the start of the low calcium dialysis and every 15 minutes until the serum calcium decreased to 7.5 mg/dl or the parathyroid hormone (Allegro, Nichols Institute, San Juan Capdialysis treatment was finished. The following week a high calcium istrano, CA, USA). Normal values are 10 to 65 pg/ml and the dialysis was performed and blood for PTH and calcium was range of the standard curve is 0 to 1400 pg/mI; when PTH values

hypocalcemia and maximally stimulate PTH and a high calcium hemodialysis (4 mEq/liter) was performed to induce hypercalcemia and maximally inhibit PTH. Blood for PTH and calcium was

obtained at the start and every 15 to 30 minutes throughout were greater than 1400 pg/ml, appropriate dilutions were performed. Serum calcium was measured at bedside during the low and high calcium studies with an automated calcium analyzer hypercalcemia, the purpose was to learn the effect that an increase (Calcette, Precision Systems mc, Natick, MA, USA). At other in the predialysis serum calcium would have on the PTH-calcium times, serum calcium and phosphorus were measured with stancurve and whether an increase in calcium due to calcitriol would dard automated laboratory techniques. be different than a calcium increase based on dialysate calcium Statistics and oral calcium supplementation. Accordingly, patients were randomized to two groups; in Group I (N = 5), patients received For comparisons among the defined parameters obtained dur2 jg of intravenous calcitriol after each hemodialysis and were ing the three low and high calcium studies, repeated measures dialyzed with a 3.5 mEq/liter calcium dialysate; in Group II (N = ANOVA was used followed by the Fisher LSD test for multiple 6), the patients were dialyzed with a 4 mEq/liter calcium dialysate comparisons. For comparisons between the two randomized and the prescribed amount of oral calcium was increased. Patients groups, the unpaired Student's t-test was used. A P value less than were maintained on their respective protocols for six weeks and 0.05 was considered significant. Results are expressed as the mean provided that the predialysis serum calcium had increased, the low SE. and high calcium studies were repeated. Three patients on the high calcium dialysate protocol and one patient receiving calcitriol Results hemodialysis.

Following the evaluation of the PTH response to hypo- and

required ten weeks for an increase in the predialysis serum

At the start of the study the mean KT/V was 1.31 0.08, and the mean predialysis hematocrit, albumin, creatinine, and serum discontinued, and the dialysate calcium and the prescribed aluminum were 28.3 1.0%, 4.0 0.1 g/dl, 12.8 0.1 mg/dl, and amount of oral calcium were changed to prestudy levels. Six weeks 19.9 4.5 jig/liter, respectively. After randomization, Groups I later the low and high calcium dialysis studies were repeated. and II were similar with respect to age (I, 47 6 vs. II, 51 7 During each of the three low and high calcium dialysis studies, years), sex (1, 3 males and 2 females vs. II, 3 males and 3 females) blood flow, dialysaie flow, and dialyzer size were the same for the and duration of dialysis (I, 65 21 vs. II, 55 13 months). As shown in Table 1, the predialysis serum calcium, PTH, phosphoindividual patient. From the data obtained during dialysis-induced hypo- and rus, and alkaline phosphatase levels were not different between hypercalcemia, the following terms were defined: (1) basal PTH the two groups after randomization, after treatment with calcitriol (PTHbase) was the predialysis PTH level; (2) maximal PTH or a high calcium dialysate, and after discontinuation of these (PTHmax) was the highest PTH level observed in response to treatments. calcium and were restudied at that time. After the second low and high calcium studies, calcitriol or the high calcium dialysate was

228

PahI et al: Set point of calcium and PTH

Table 1. Biochemical data in the two groups at three intervals PRE'

I

I

/

POST1'

POSTb

II

A

II

I

II

n=5

n=6

n=5

n=6 n=5 n=6

992±

810±

642±

610±

935±

908±

257 9.62±

266 9.19±

265

409

362

9.84±

0.31

5.12±

6.17±

6.12±

0.28 6.00±

0.61

0.73

0.71

1.10

9.94± 0.29 5.96± 0.65

9.26±

0.34

285 10.56± 0.31

445±

297±

441±

280±

399±

247±

300

69

357

81

319

70

+

Serum

PTH (pg/mI) Calcium (mg/dl) Phosphorus (mg/dl) Alkaline Phosphatase

0.26

5.90± 0.76

(lU/L)

Calcitriol

Mean SE PRE—before calcitriol (I) or a high calcium dialysate (II) h POST—after treatment with calcitriol (I) or a high calcium dialysate (II)

Calcium

Combined

Calcium

Combined

B

POST1—after discontinuation of calcitriol (I) or a high calcium

dialysate (II) E

Table 2. Biochemical data in the calcitriol group.

PRE PTHmax (pg/mI) PTHbase (pg/mI) PTHmin (pg/mI) Basal/Max PTH (%) Mm/Max PTH (%) Basal Calcium (mg/dl) Set Point of Calcium (mg/dl) CArnax (mg/dl) CAmin (mg/dl)

2637 687 992 257 584 214

40 6 21 4

POST5 1555

617*

642 285 495 290

36 7 24 5

9.62 9.34

.34 .23

10.56

.31t

9.79

.25*

8.47

.28 .17

8.14

.25 .28

POST1C

2441 896

935 409 428 185

36 10 17 3

9.94 9.55

.24

8.26

.29

10.91

.33

.29

E S

0 It 0

0 C

0 a

°' 8.5 Calcitriol

10.86

11.03

Mean SE *p < 0.05 versus PRE tP < 0.05 versus PRE and POST PRE—before calcitriol POST—after treatment with calcitriol POST1—after discontinuation of calcitriol

Fig. 1. Effect of treatment with calcitriol, treatment with a high calcium dialysate, or a combination of both groups on the basal (predialysis) serum calcium (A) and the set point of calcium (B) is shown. Symbols are: (III, pre) post) at the end of six weeks of treatment; (i2, post-i) six weeks after treatment was discontinued; * < 0.05 vs. pre; +P <0.05 vs. pre and post-i.

before treatment; (,

calcium, the set point of calcium, and the maximal PTH to As shown in Table 2 and Figure 1, calcitriol treatment combined with a dialysate calcium of 3.5 mEq/liter (Group 1) resulted in an increase in the basal calcium from 9.62 0.34 to 10.56

baseline values. Since the results of the studies on the effect of increasing the predialysis (basal) serum calcium were similar in both groups, the

groups were combined to increase the power of analysis. After 0.31 mg/dl, P < 0.05. Treatment with calcitriol resulted in a either calcitriol treatment or an increased calcium dialysate with decrease in maximal PTH (P < 0.05) and tended to decrease basal oral calcium supplementation, the basal serum calcium increased (P = 0.08 by repeated measures ANOVA) (Fig. 2). Despite this from 9.39 0.24 to 10.17 0.24 mg/dI, P < 0.001 (Fig. 1). At the reduction in PTH, the set point of calcium increased (P < 0.05; same time as the serum calcium increased, both basal PTH (P < Fig. 1). Discontinuation of calcitriol resulted in a return of the 0.02) and maximal PTITI (P < 0.005) decreased (Fig. 2). Despite basal calcium, the set point of calcium, and the basal and maximal the reduction in basal and maximal PTH, the set point of calcium increased (P < 0.001; Fig. 1). The discontinuation of calcitriol and PTH to values similar to baseline. As shown in Table 3, results in the high calcium dialysate group a high calcium dialysate with oral calcium supplementation re(Group II) were similar to those of the calcitriol treatment group sulted in a return of the basal calcium, the set point of calcium, (Group I). An increase in the dialysate calcium concentration and and the basal and maximal PTH to values not different than oral calcium supplementation increased the basal calcium from baseline. 9.19 0.31 to 9.84 0.28, P < 0.05 (Fig. 1). A high calcium Discussion dialysate combined with oral calcium supplementation resulted in

a decrease (P < 0.05) in maximal PTH (Fig. 2). Despite the

In the present study in hemodialysis patients with secondary

decrease in maximal PTH, the set point of calcium increased (P < hyperparathyroidism, treatment with either calcitriol or a high 0.05; Fig. 1). Discontinuation of the high calcium dialysate and calcium dialysate increased the predialysis (basal) serum calcium.

oral calcium supplementation resulted in a return of the basal

Both treatments also resulted in a decrease in PTH levels, but

229

Pahi et al: Set point of calcium and PTH Table 4. Biochemical data in the two groups combined.

A

PRE* PTHmax (pg/mI) PTHbase (pg/mi) PTHmin (pg/mi) Basal/Max PTH (%) Mm/Max PTH (%) Basal Calcium (mg/dl) Set Point of Calcium (mgldl) CAmax (mg/dl) CAmin (mg/dl)

Calcitriol

Mean

Combined

Calcium

2094

427

893 437

188 135

43 18 9.39 9.16

4 3

8.42 10.74

POST5

1443 395j

POST1' 2061 920 360

529

.18f

9.57 9.28

.22 .19

.18 .18

8.14 10.80

.18

625 378

193* 152

.24 .19

21 10.17 9.57

3 .24l

.22 .18

8.19 10.92

36 6

270 113

41 6 16 2

.23

SE

*p < 0.02 versus PRE and POST

tP < 0.005 versus PRE and POST PRE—before caicitriol (I) or a high calcium dialysate (II) POST—after treatment with calcitriol (I) or a high calcium dialysate

B

(II) 1500

POSTI—after discontinuation of caicitriol (I) or a high calcium

dialysate (II)

0

Calcium Combined

Calcitriol

Fig. 2. Effect of treatment with calcitriol, treatment with a high calcium dialysate, or a combination of both groups on the maximal PTH level (A) and the basal (predialysis) PTH level (B) is shown. Symbols are: (, pre) before treatment; (, post) at the end of six weeks of treatment; (ui, post-i) six weeks after treatment was discontinued; *P < 0.05 vs. pre; +P < 0.05 vs.

pre and post-i.

magnitude of hyperparathyroidism and is likely influenced by the ambient serum calcium concentration. The meaning of the set point of calcium has been debated since the term was first popularized by Brown et al more than a decade ago. In an elegant series of in vitro studies, Brown et al demonstrated that the set point of calcium was greater in adenomatous and hyperplastic than normal parathyroid glands [10, 11]. Thus, the concept evolved that the set point of calcium was an indicator

of the mass of the parathyroid gland. However, it should be emphasized that the in vitro testing of the PTH-calcium relation-

ship is performed in a closed system that is not influenced by factors other than the externally manipulated calcium concentra-

tion. In normal humans and animals, the ability of PTH to modulate serum calcium is affected by calcium absorption from

the gut, calcium deposition and release from bone, and renal

Table 3. Biochemical data in the high calcium diaiysate group.

PRE PTHmax (pg/mi) PTHbase (pg/mi) PTHmin (pg/mi)

Basai/MaxPTH(%) Mm/Max PTH (%) Basal Calcium (mgldl) Set Point of Calcium (mgldl) CAmax (mg/dl) CAmin (mg/dl)

Mean

*p <

1642 810 315

450 266

14 9.19

4

9.01

8.38 10.64

155

44±6

POST' 1349

513t

1744

595

610 279

265

908 304

362

128

18

136

45±7

36±12

14

5

.28t

.28

9.84 9.39

.22*

9.26 9.07

.33 .28

8.24 10.82

.26 .22

10.71

.31

excretion of calcium. Moreover, differences in the potency of PTH

POST1C

8.05

3 .26 .23 .21 .32

SE

versus PRE versus PRE and POST tP < a PRE—before a high calcium dialysate h POST—after treatment with a high calcium dialysate POST1—after discontinuation of a high calcium dialysate 0.05 0.05

despite the reduction in PTH, an increase in the Set point of calcium was observed. Discontinuation of the calcitriol or the high

become apparent when normal individuals and hemodialysis patients are compared; for the same serum calcium concentration, the PTH level in the hemodialysis patient may be 20 to 40 times greater [5, 21]. Thus, it is our opinion that in the in vivo setting, the set point of calcium may best be considered to be an indicator of

the serum calcium concentration at which PTH secretion is stimulated [5]. In a recent publication, Brown has also arrived at a similar conclusion for the meaning for the set point of calcium in in vivo studies [22]. While we believe that the set point of calcium is consistently an

indicator of the serum calcium concentration at which PTH secretion is stimulated, the set point of calcium may also be in certain situations an indicator of the magnitude of hyperparathyroidism. In individuals with normal renal function, the set point of calcium is increased in patients with primary hyperparathyroidism as compared with normal individuals. In this situation, the higher PTH levels increase the serum calcium by enhancing bone resorption, augmenting renal calcium reabsorption, and increasing gut of absorption of calcium through the action of PTH on calcitriol production [23, 24]. In renal failure because of skeletal resistance to PTH [13], diminished renal modulation of calcium excretion

calcium dialysate resulted in a return of the predialysis serum calcium, the set point of calcium, and PTH to pretreatment values. The finding that the set point of calcium increased at the [14], and decreased calcitriol levels [15], regulation of serum same time as PTH levels decreased would suggest that the set calcium is more problematic and less precise than in normal point of calcium may not necessarily be an indicator of the individuals. This concept is well-illustrated in the recent study by

230

PahI et al: Set point of calcium and PTH

Messa et al in which three groups of patients with progressive In conclusion, the results of the present study in hemodialysis renal failure were characterized [251. As expected, PTI-I levels patients have demonstrated that treatment with either calcitriol or increased as renal function decreased, but the set point of calcium a high calcium dialysate can increase the set point of calcium for the three groups was similar despite more than a sixfold despite a decrease in the PTH level. These results would suggest difference in PTH levels. Further complicating the situation in that the set point of calcium may not be a reliable indicator of the renal failure are the different forms of renal osteodystrophy which magnitude of hyperparathyroidism during calcitriol treatment in are characterized by low or high bone turnover [26]. In dialysis hemodialysis patients. Furthermore, the results of this study patients with a relative PTH deficiency and low bone turnover suggest the intriguing possibility that PTH secretion by the such as in adynamic bone or aluminum associated osteomalacia, parathyroid gland may adapt to the ambient serum calcium the set point of calcium tends to be lower than in dialysis patients concentration. with markedly increased PTH levels and the high-turnover bone disease, osteitis fibrosa [19]. However, complicating calcium regulation in the dialysis patient are several confounding variables

Acknowledgment

which include an inability to modulate serum calcium when The authors thank Ms. Roma Fuller for her invaluable assistance and dialysis patients with low bone turnover are challenged with a care in the preparation of the special dialysis baths which were necessary calcium load [271, the effect of hyperphosphatemia on calcium for the performance of this study. regulation [15], and marked differences in active and quiescent bone surfaces among patients [281. Reprint requests to Arnold J. Felsenfeld, M.D., Nephrology Section Some studies in hemodialysis patients have suggested that since (W11JL), West Los Angeles VA Medical Center, 11301 Wilshire Boulevard, the calcitriol-induced reduction in PTH levels is accompanied by Los Angeles, California 90073, USA. a reduction in the set point of calcium, the set point of calcium reflects a reduction in the magnitude of hyperparathyroidism [3, References 7]. However, a reduction in the set point of calcium has not been

observed in all studies in dialysis patients in which calcitriol treatment redued PTH levels [2, 4, 8, 9] or even in a study in azotemic patients in which phosphorus restriction reduced PTH levels [29].

The present study was specifically designed to increase the serum calcium concentration and decrease PTH levels, and to evaluate how these changes affected the set point of calcium. Despite the reduction of PTH levels, the higher predialysis (basal)

calcium resulted in an increase in the set point of calcium. Calcitriol treatment in the present study was different than in previous studies in which the goal was to prevent hypercalcemia and as a result, the dialysate calcium was reduced. Consequently in those studies, significant increases in the serum calcium were prevented or were only modest [2—41. The finding that the set point of calcium can increase at the same time PTH levels are

reduced would appear to adequately demonstrate that the set point of calcium does not necessarily reflect the magnitude of hyperparathyroidism.

The set point of calcium increased at the same time as the predialysis calcium increased and PTH levels decreased. This result raises the intriguing question whether after a certain length of time, PTH secretion by the parathyroid gland adapts to the ambient serum calcium. Previous studies have shown the set point of calcium to be higher in primary hyperparathyroidism than in

normals [24], and in dialysis patients with marked secondary hyperparathyroidism than in dialysis patients with lesser degrees

of PTH elevation [19]. These results were at least in part

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