Hypercalcemia During Pulse Vitamin D3 Therapy in CAPD

Patients Treated with Low Calcium Dialysate: The Role of the

Decreasing Serum Parathyroid Hormone Level

AVRY CHAGNAC,* YAACOV ORL�K TALIA WEINSTEIN,* DINA ZEVIN,*

ASHER KORZETS,* JUDITH HIRSH,* SAMUEL EDELSTEIN,� and UZI GAFTER**Department of Nephrology, Rabin Medical Center, Golda Campus, Petah-Tikva, israel, and �Departinent of

Biochemistry, The Weizmann institute of Science, Rehovot, israel.

Abstract. Oral pulse therapy with vitamin D is effective in

suppressing parathyroid hormone (PTH) secretion in continu-

ous ambulatory peritoneal dialysis patients with secondary

hyperparathyroidism (2’hpt). However, this treatment often

leads to hypercalcemia. The goals of the study were: (1) to

examine whether the incidence of hypercalcemia decreases

when dialysate calcium is reduced from 1 .25 to 1 .0 mmol/L;

(2) to determine the relative role of the factors involved in the

pathogenesis of hypercalcemia; and (3) to study the efficacy of

a low oral pulse dose of alfacalcidol in preventing the recur-

rence of 2’hpt. Fourteen continuous ambulatory peritoneal

dialysis patients with 2’hpt were treated with pulse oral alfa-

calcidol and calcium carbonate and dialyzed with a 1 .0-mmol

(n 7) or a I .25-mmol (n = 7) dialysate calcium. The

response rate (87%) and the incidence (71 %) and severity of

hypercalcemia were similar in both groups. In the early re-

spomse stage, PTH decreased by 70% in both groups, and

serum ionized calcium (iCa) increased from 1 . 18 ± 0.02 to

1.27 ± 0.04 mmol/L (P < 0.005) in the 1.0 group and from

1 . 19 ± 0.02 to 1 .29 ± 0.02 mmol/L in the 1 .25 group (P <

0.005). Nine of the 12 responders had a further decrease in

serum PTH, which was associated with an additional increase

in iCa from 1 .28 ± 0.02 to I .47 ± 0.04 (P < 0.005). Multi-

variate analysis showed that the early increase in iCa was

positively correlated with alfacalcidol dosage (r = 0.69). In

contrast, the late increase in iCa was mostly accounted for by

the decrease in serum PTH (r = -0.93). This occurred while

calcium carbonate, alfacalcidol dosage, and serum I ,25 hy-

droxy D3 remained unchanged compared with the early re-

sponse stage. Finally, an alfacalcidol dose of 1 jig twice

weekly was unable to maintain serum PTH at am adequate level

in the long term. These data show that a reduction in dialysate

calcium from 1 .25 to 1 .0 mmol does not reduce the occurrence

of hypercalcemia and suggest that lowering serum PTH re-

duces the ability of the bone to handle a calcium load within a

few weeks, thus causing hypercalcemia. (J Am Soc Nephrol 8:

1579-1586, 1997)

Secondary hyperparathyroidism occurs in approximately one-

third of patients on continuous ambulatory peritoneal dialysis

(CAPD) ( 1,2). Intermittent therapy with a high dose of an

active vitamin D sterol, administered intravenously or orally, is

effective in suppressing parathyroid hormone (PTH) secretion

in hemodialysis (3-13) and CAPD patients (14-17) with sec-

ondary hyperparathyroidism. However, a setback of this treat-

ment is that it requires the administration of high doses of

phosphate binders (13). Because aluminum-containing phos-

phate binders have side effects, calcium carbonate has been

used mainly to control hyperphosphatemia. The concomitant

use of calcium carbonate and high-dose vitamin D leads to

frequent episodes of hypercalcemia (1 1,12,16-20), which

hamper the benefits of this treatment. To enable the use of oral

Received September 9, 1996. Accepted January 26, 1997.Correspondence to Dr. Uzi Gafter, Department of Nephrology and Hyperten-

sion, Rabin Medical Center, Golda (Hasharon) Campus, 7 Keren KayemetStreet, Petah-Tikva 49372, Israel.

1046-6673/08010- 1579$03.00/0Journal of the American Society of Nephrology

Copyright © 1997 by the American Society of Nephrology

pulse vitamin D therapy in CAPD patients, the dialysate cal-

cium has been decreased from 1 .75 to 1 .25 mmolfL (18,20).

However, this reduction has not eliminated hypercalcemia ep-

isodes, and therefore pulse therapy is still often given in

combination with aluminum-containing phosphate binders.

The first aim of the study presented here was to investigate

whether a further reduction of dialysate calcium to I .0 mmollL

would enable pulse alfacalcidol therapy while reducing the

frequency of hypercalcemic episodes, thereby avoiding the

need for aluminum-containing phosphate binders.

Multiple factors may be involved in the pathogemesis of

hypercalcemia. These include vitamin D3 and calcium carbon-

ate therapy, dialysate calcium concentration, serum PTH level,

and bone activity. The second aim of this study, therefore, was

to examine the respective role of these factors in the develop-

ment of hypercalcemia during the course of oral vitamin D3

pulse therapy.

Still unresolved is the question of how much alfacalcidol

should be administered to maintain serum PTH at an adequate

level (two to three times the upper normal limit) after am initial

response has been obtained. It has been suggested that vitamin

D should not be given unless PTH rises above this limit.

1580 Journal of the American Society of Nephrology

However, this might not be adequate for patients who reach

this range after receiving pulse vitamin D therapy (21). Thus,

the third aim of the study was to determine whether a low dose

of alfacalcidol administered as pulse therapy could keep PTH

at required levels, after the initial reduction has been achieved.

Materials and MethodsPatients

Fourteen nondiabetic CAPD patients participated in the study.

They had been on CAPD for I to 5 yr. There were I 3 men and I

woman, aged 22 to 84. Their serum intact PTH was above 165 pg/ml,

which is more than 3 times the upper normal limit. All of them had

been dialyzed with a 1 .25-mmol dialysate calcium and had received 0

to 0.5 � of alfacalcidol daily and calcium carbonate as a phosphate

binder. Two had also been given sucralfate at a dose of 2 g/d before

enrollment and were maintained on the same dose throughout the

study. Aluminum intoxication was ruled out in these two patients by

a standard desfemoxamine test (22). These 14 patients were random-

ized into two groups after matching for serum PTH. Seven patients

were started on a I .0-mmol dialysate Ca ( 1 .0-mmol group), and seven

were maintained on a l.25-mmol dialysate Ca (l.25-mmol group).

The characteristics of the two groups before the start of the study are

summarized in Table I.

Study Design

The patients were started on oral pulse therapy with alfacalcidol ata dosage of 2 �g twice weekly. The dose was increased every 2 wk

to 3, 4, and 5 i.�g twice weekly, unless hypercalcemia occurred. Serum

phosphorus was maintained below 5.5 mg/dl by increasing the cal-

cium carbonate dose when necessary. Serum was sampled every 2 wk

for biochemical assessment. The maximal alfacalcidol dose not caus-ing hypercalcemia was maintained at least for the first 12 wk of the

study. However, when mild hypercalcemia (serum ionized calcium

[iCa] above I .3 and below 1 .35 mmollL) occurred while the patient

was on the 2-pg dose, pulse therapy was continued at this dose despite

hypercalcemia. A response was defined as a decrease in serum PTH

below 165 pg/ml, i.e., below 3 times the upper limit of normal.

Patients who responded (referred to as responders) had the alfacal-

cidol dose decreased to 1 �g twice weekly. In patients in whom serum

PTH decreased below 1 10 pg/mI, i.e., twice the upper normal limit,

alfacalcidol therapy was discontinued until PTH reached a value 2 to

3 times the upper normal limit. Alfacalcidol was then resumed at a

dose of I ,.tg twice weekly. Nonresponders at 12 wk were maintained

on the maximum tolerated dose. Treatment was discontinued at 12 wk

in nonresponders if the maximum tolerated alfacalcidol dose was the2-pg, twice weekly dose given initially.

The response data were analyzed at two different periods. The earlyresponse phase was defined as the time when serum PTH decreased

for the first time below 165 pg/ml. After this initial decrease, the data

of those responders who had a further reduction in serum PTH were

also analyzed at the time of lowest PTH; this period was referred to as

the late response phase.

Biochemistry

iCa, phosphorus, and alkaline phosphatase were measured by stan-

dard laboratory techniques (normal values: 1 . 1 to 1 .3 mmollL, 2.7 to

4.5 mg/dl, and 39 to 1 17 UIL, respectively). Serum levels of PTH

were determined by the immunoradiometric assay for intact human

PTH, using the N-tact PTH SP kit (Incstar, Stillwater, MN) (normalvalues: 13 to 54 pg/ml). Serum levels of l,25-dihydroxyvitamin D3

were determined using a microassay (23) (normal values: 20 to 50

pg/mI).

Statistical Analyses

Results are expressed as the mean ± SEM. All tests were two-

sided. Comparisons between the two groups were made using un-

paired and paired t tests. P < 0.05 was considered significant. When

three groups were compared, ANOVA for repeated measurements

was applied before the t test, and Bonferroni correction was made

(P < 0.01 was considered significant). Possible relationships between

four independent parameters and iCa as a dependent variable were

analyzed by linear correlation. Logistic regression using forward

stepwise selection was performed, using the Statistical Package for

Social Sciences software package. Serum PTH was log-transformed

for the linear regression analysis.

ResultsTable 1 shows the characteristics of the patients in the two

groups. They were comparable for age, sex distribution, time

on dialysis, baseline iCa, serum phosphorus, and PTH. After 12

wk, 1 1 patients had responded: five of seven (71%) in the

1 .0-mmol group and six of seven (87%) in the 1 .25-mmol

group (P, NS). They were then placed on low-dose alfacalcidol

maintenance therapy. A twelfth patient, who belonged to the

1 .0 group, responded at week 1 8 and was then placed on

low-dose alfacalcidol. Two patients, one in each group, did not

respond at 12 wk while they were on 2 p.g of alfacalcidol twice

weekly. The mean iCa, phosphorus, and PTH of the two

nonresponders during the treatment period (weeks 2 to 12)

were 1.33 ± 0.01 mmollL, 5.6 ± 0.6 mg/dl, and 524 ± 80

pg/mI, respectively. Because the alfacalcidol dose could not be

increased because of hypercalcemia, they were considered

nonresponders.

The maximal alfacalcidol dose administered to the respond-

ers was 4.7 ± 0.2 p.g in the 1.0 group and 3.8 ± 0.4 p�g in the

1 .25 group (P, NS). The time lapse to response was 7.0 ± 2.7

wk in the 1 .0 group and 5.0 ± 1 . 1 wk in the 1 .25 group (P,

NS). PTH decreased by 70% in both groups, from 357 ± 5 1 to

108 ± 9 pg/ml in the 1 .0 group (P < 0.01) and from 342 ± 64

to 101 ± 17 pg/ml in the 1.25 group (P < 0.02) (Figure 1). In

the early response phase, iCa increased similarly in the two

groups, from 1 . 18 ± 0.02 to 1 .27 ± 0.04 mmollL in the 1.0

group (P < 0.005) and from 1.19 ± 0.02 to 1.29 ± 0.02

Table 1. Patient’s characteristics at baselin&’

Characteristic 1.0 Group 1.25 Group P

n 7 7

Age 60±7 73±3 NS

Sex (M/F) 7/0 6/1 NS

Time on CAPD (mo) 2 1 ± 5 26 ± 7 NS

Serum PTH (pg/ml) 420 ± 76 349 ± 55 NS

Serum iCa (mmolIL) I .2 1 ± 0.03 1 .2 1 ± 0.03 NS

Serum P (mg/dl) 4.6 ± 0.3 4.9 ± 0.1 NS

a CAPD, continuous ambulatory peritoneal dialysis; iCa, serum

ionized calcium; P, phosphorus.

P < 0.01

1.25 group

P < 0.02

1.0 group

E0)

0.

II-

600 -

500 -

400 -

300 -

200 -

100 -

0-

1.4 -

P < 0.005 P < 0.005

/1.2 -

1.1 -

1-1.0 group

Baseline EarlyResponse

1 .25 group

Baseline EarlyResponse

Pulse D3 and Hypercalcemia: The Role of PTH 1581

:J�� 1.3

0

E

c�j0�0ci)NC0

1.0 group

Baseline EarlyResponse

1.25 group

Baseline EarlyResponse

Figure 1. Serum PTH in 12 responders at baseline and early response.

Figure 2. Serum ionized calcium (iCa) in 12 responders at baseline and early response.

mmol/L in the 1 .25 group (P < 0.005) (Figure 2). Serum

phosphorus was similar at baseline and at early response in

both groups (4.7 ± 0.3 and 4.8 ± 0.3 mg/dl, respectively, in

the 1 .0 group and 4.9 ± 0.1 and 4.7 ± 0.9 mg/dl, respectively,

in the 1 .25 group). Among the responders, hypercalcemia

occurred in two-thirds of the patients (4 of 6) in the 1 .0 group

1582 Journal of the American Society of Nephrology

and in all of the patients (6 of 6) in the 1 .25 group (P, NS). All

episodes of hypercalcemia in the responders occurred after

they had responded ( I .5 ± I wk after response in the I .0 group

and 2.0 ± 0.5 wk after response in the I .25 group; P. NS).

Mean iCa at the time of first occurrence of hypercalcemia was

1.45 ± 0.06 mmolfL in the 1.0 group and 1.37 ± 0.01 mmollL

in the 1 .25 group (P, NS). Mean serum PTH at this time was

57 ± 26 pg/mI in the 1.0 group and 47 ± 6 pg/ml in the I .25

group (P, NS).

After the initial decrease in PTH (early response phase), nine

of the I 2 responders had a further decrease in serum PTH while

they were maintained on pulse alfacalcidol until week I 2 (late

response phase). Table 2 shows values for iCa, PTH, and doses

of alfacalcidol and calcium carbonate at early and late response

phases for these nine patients. Despite the fact that alfacalcidol

and calcium carbonate doses, as well as serum I ,25-dihy-

droxyvitamin D3, were similar during these two periods, the

decrease in serum PTH from 1 14 ± 10 to 3 1 ± 6 pg/ml was

associated with an increase in iCa from 1 .28 ± 0.02 to 1 .47 ±

0.04 mmol/L (P < 0.005). Table 3 shows the changes in iCa

and alkaline phosphatase for these nine patients at baseline,

early, and late phases, depicting the concomitant changes in

these variables. These findings show that the decrease in serum

PTH was associated with an increase in iCa to the high-normal

range in the early response phase, and with a further increase

in the late response phase. To investigate the respective role of

the factors that could be involved in the regulation of iCa, we

performed a regression analysis of four variables (serum PTH,

dialysate calcium, alfacalcidol, and calcium carbonate dose)

over iCa. Figure 3 shows the regression of serum PTH over iCa

at baseline and early and late response phases, revealing that

changes in PTH accounted for 79% of the changes in iCa. A

separate analysis was performed for the first period (baseline

and early response phases, 12 patients, n = 24) and the second

period (early and late response phases, nine patients who had a

further decrease in PTH after initial response, n = I 8). Results

for umivariate regression analysis are shown in Table 4. During

the first period, alfacalcidol dosage and serum PTH accounted

each for 47 to 48% of the variation in iCa, with serum PTH

negatively correlated. Calcium carbonate dose accounted for

only 22% of the variation. The multivariate analysis showed

Table 3. iCa and alkaline phosphatase at baseline and early

and late response phasesa

Variable BaselineEarly Response

PhaseLate Response

Phase

Serum iCa 1 . 1 8 ± 0.02 1 .28 ± 0.02�’ 1 .47 ± 004a,b

(mmol/L)

Alkaline 93 ± 6 89 ± 9 76 ± 7C

phosphatase

(U/L)

a p < 0.001 versus baseline.b p 0.001 versus early response.C p 0.001 versus baseline.

that addition of other variables did not increase the predictive

value of alfacalcidol dosage for calcemia: iCa = 0.03 alfacal-

cidol dose + 1.19, r = 0.69, r = 8%, P < 0.001.

During the second period, univariate analysis revealed that

serum PTH was negatively correlated with iCa, accounting for

86% of its variation. Alfacalcidol dosage had a much weaker

correlation, accounting for only 30% of the iCa variation.

Multivariate analysis showed that serum PTH and alfacalcidol

dosage were independently correlated with iCa, together ac-

counting for 94% of its variation: iCa = 0.04 alfacalcidol

dose - 0.29 Log PTH + 1.75, r = 0.97, r� = 94%, P < 0.001.

Eleven of the 1 2 responders were maintained on 1 p.g of

alfacalcidol twice weekly, after they had responded. As shown

in Figure 4, serum PTH had increased to more than 3 times the

upper limit of normal in 55% of the patients at 6 wk of

maintenance therapy and in all of the patients at 46 wk.

DiscussionThe present study shows, in accordance with previous re-

ports, that oral pulse therapy with an active vitamin D3 sterol

is an efficient treatment for secondary hyperparathyroidism in

CAPD patients, decreasing PTH secretion in approximately

80% of the patients. Decreasing calcium dialysate from I .25 to

1 .0 mmol did not reduce the incidence and severity of hyper-

calcemia. The pathogenesis of hypercalcemia during the early

response phase differed from that seen in the late response

Table 2. Serum PTH, iCa, alfacalcidol, and calcium carbonate doses at early and late response phases in nine patients whose

serum PTH decreased into the low to normal range during alfacalcidol pulse therapy�’

-Variable

Early ResponsePhase

Late ResponsePhase

P Value

Time from start of pulse therapy (wk) 3.6 ± 0.6 8.7 ± 0.9 *“

Serum PTH (pg/ml) 114 ± 10 31 ± 6 *b

Serum iCa (mmolIL) 1.28 ± 0.02 1.47 ± 0.04 <0.005

Serum P (mg/dl) 4.5 ± 0.3 5.2 ± 0.3 <0.05

Serum l,25-dihydroxy D3 (pg/ml) 58 ± 16 57 ± 7 NS

Alfacalcidol dose (p.g/twice/wk) 2.8 ± 0.3 3.0 ± 0.3 NS

Calcium carbonate dose (mg/d) 2760 ± 460 2200 ± 320 NS

a Abbreviations as in Table I.

h *, different by definition.

A

aah

0.79

-J

0

E

C’,

0�0ci)NC0

P<0.001

A

U

. U�JA

.

cm . 0

0 0.

0

0.

I I I

50 100 500 1,000

Pulse D3 and Hypercalcemia: The Role of PTH 1583

1.7

1.6 -

1.5 -

1.4 -

1.3 -

1.2 -

1.1

110

PTH (pg/mL)

y=-0.25 log x +1.8

r=-0.89

Figure 3. Correlation between serum PTH (log units) and iCa in 12 responders at three time periods: baseline (n = 12, circles), early response

(n 12, squares), and late response (n = 9, triangles). Open symbols, l.0-mmol group; closed symbols, l.25-mmol group.

Table 4. Univariate regression analysis of four variables over serum iCaa

VariableFirst Period (n = 24) Second Period (n = 18)

r �2 p Value r r� P Value

Serum PTH -0.68 0.47 <0.001 -0.93 0.86 <0.001

Alfacalcidol dose 0.69 0.48 <0.001 0.55 0.30 <0.01

Calcium carbonate dose 0.47 0.22 <0.05 -0.05 0.003 NS

Dialysate calcium 0.08 0.01 NS 0.12 0.02 NS

a The first period includes baseline and early response phases (12 patients, 24 measurements). The second period includes early and late

response phases (nine patients, 18 measurements).

period. After a response had been obtained, administration of a

low-maintenance dose of I �g of alfacalcidol twice weekly

was not effective in keeping PTH serum levels in the desired

range.

In early studies with pulse vitamin D3 in which aluminum

hydroxide was the main phosphate binder, hypercalcemia was

not reported as a major problem (4,6-8). An adequate control

of serum phosphate is necessary during treatment of secondary

hyperparathyroidism, because hyperphosphatemia directly

stimulates PTH secretion (13,24-26), thus reducing the effi-

ciency of pulse therapy (1 3), and increases the calcium-phos-

phate product, causing extraosseous calcificatioms. Because the

dangers of aluminum accumulation have become apparent,

calcium salts have replaced aluminum hydroxide as the phos-

phate binder of choice. However, this substitution often led to

episodes of hypercalcemia ( 1 1 , I 2, 16-20). This complication

may be avoided by using one or more of the following options:

(1) decreasing the calcium carbonate dosage (however, this

would result in increased serum phosphorus concentration); (2)

reducing calcium salts dosage and adding aluminum-contain-

ing phosphate binders, with the risks associated with an alu-

minum burden; (3) decreasing dialysate calcium to enable the

elimination of the excess calcium absorbed by the gut (27).

Cunningham et a!. (28) succeeded in avoiding hypercalcemia

in most CAPD patients treated with calcium carbonate and no

vitamin D by decreasing calcium dialysate from 1.75 to 1.45

mmol, and in some cases to 1 .0 mmol. However, the addition

of daily low-dose alfacalcidol resulted in hypercalcemia in

more than 20% of the patients despite a reduction in calcium

dialysate to 1 .0 mmol. Only a decrease in calcium dialysate to

0.6 mmol eliminated hypercalcemia in all of the patients

treated with calcium carbonate and low-dose daily alfacalcidol

100

75

50

25

0

n=5

n=4

n=3

0

n=2

n=1

3010 20

Weeks after start of maintenance therapy

40

Figure 4. Kaplan-Meier curve showing the proportion of responders still in remission during maintenance pulse therapy with low-dose

alfacalcidol ( I p�g, twice weekly).

50

1584 Journal of the American Society of Nephrology

>�0�

C���.2 ci�U)

cDt�c’j

( 18). Hutchison and Gokal (20) also demonstrated a decrease

in the incidence of hypercalcemia when they decreased cal-

cium dialysate from 1 .75 to 1 .25 mmol. However, the effec-

tiveness of these low calcium solutions as a method of decreas-

ing the incidence of hypercalcemia during oral pulse therapy

has not been tested previously.

The present study was designed to verify whether I .0-mmol

calcium solutions would decrease the incidence of hypercalce-

mia during oral pulse therapy. Serum phosphorus was ade-

quately controlled with calcium carbonate, due to a stepwise

increase in alfacalcidol and calcium carbonate dose. Hypercal-

cemia occurred at a similar rate in the I .0- and 1 .25-mmol

calcium groups and was equally severe in the two groups. PTH

decreased similarly. Two patients, one in each group, could not

receive high alfacalcidol dose because of hypercalcemia, and

did not respond. These findings suggest that a 20% decrease in

dialysate calcium is insufficient to enable oral pulse therapy

without the occurrence of hypercalcemia. The use of a dialy-

sate with a calcium concentration lower than 1 .0 mmol could

allow an increase in vitamin D3 dosage in those patients who

had hypercalcemia at the relatively low alfacalcidol dose of

2 j.�g twice weekly. It could also attenuate the incidence and

severity of hypercalcemia in patients treated with higher alfa-

calcidol doses.

In the two monresponders, serum PTH did not decrease

despite mild hypercalcemia. Because uremic patients need a

slightly elevated iCa to achieve inhibition of PTH secretion,

the two nonresponders were maintained on alfacalcidol despite

the increased iCa. The lack of response in these two patients

was in part due to the low alfacalcidol dose administered. To

prevent a further rise in iCa, this low dose was not increased.

The hypercalcemia occurring at low alfacalcidol dosage in

these two monrespomders could either reflect the severity of the

secondary hyperparathyroidism, or, on the contrary, be the

consequence of an aplastic bone state. Although this is very

unlikely considering the serum PTH level, it cannot be entirely

ruled out, because bone biopsies were not performed.

The observed decrease in serum PTH in the responders was

associated with an increase in iCa. Often, serum PTH de-

creased below the target level of 2 to 3 times the upper normal

limit. This overshooting was usually associated with the oc-

curremce of hypercalcemia. This relationship between serum

PTH and calcium has been reported by Slatopolsky et al. (4) in

the first study investigating the effects of intermittent 1,25-

dihydroxycalciferol therapy in patients with secondary hyper-

parathyroidism. More recently, Quarles et al. (12) showed that

increases in iCa predicts decrements in serum PTH during

intermittent calcitriol therapy. However, the pathogenesis of

this increase in iCa has not been elucidated. The relative role of

the different factors that may be responsible for this increase,

such as vitamin D dose, calcium salts dose, serum PTH,

dialysate calcium concentration, and bone activity, has not

been determined. In the present study, the similar rate and

severity of hypercalcemia in the groups with 1 .0 and 1.25

mmol of dialysate calcium and the lack of correlation between

iCa and dialysate calcium suggest that the variation in dialysate

calcium did not account for the changes in iCa. Multivariate

analysis revealed that the factors that had been independently

correlated with iCa differed during the early and late periods of

pulse therapy. During the first period, when serum PTH de-

creased from baseline to a value of twice the upper normal

limit, changes in alfacalcidol dosage accounted for most of the

changes in iCa, whereas serum PTH and the calcium carbonate

dosage were found not to be independently correlated with

calcemia. In contrast, during the late period, when serum PTH

further decreased to the normal level, the main factor whose

changes accounted for the changes in iCa was serum PTH,

which was negatively correlated, explaining 86% of the cal-

Pulse D3 and Hypercalcemia: The Role of PTH 1585

cium variation. Alfacalcidol dosage was also independently

correlated, although much more weakly, increasing the r� to

94%.

The fact that few cases of hypercalcemia occurred during the

first treatment period may be explained by several factors: the

population studied had mild to moderately severe hyperpara-

thyroidism, with a mean serum PTH of approximately 7 times

the upper normal limit; dialysate calcium was equal to or less

than the normal iCa concentration; alfacalcidol dose was in-

creased stepwise, allowing an adjustment of the vitamin D and

calcium carbonate dose according to the iCa and phosphorus

concentrations. The strong negative correlation between serum

PTH and calcium when serum PTH decreased below the target

level does not in itself point to a cause-and-effect relationship.

However, the finding that iCa was higher during the late

response phase compared with the early response phase,

whereas alfacalcidol and calcium carbonate dosages were sim-

ilar, suggests that the decrease in serum PTH to below the level

of twice the upper normal limit was the maim pathogenic factor

that increased iCa. This is in accordance with the known

effects of PTH on bone turnover (29 -3 1). Suppressed PTH

levels are associated with low bone turnover osteodystrophy

and high iCa (29). Goodman et al. (30) demonstrated that

adynamic bone develops in 50% of children and adolescents

with secondary hyperparathyroidism after 12 mo of intermit-

tent calcitriol therapy. The adynamic bone is characterized by

a state of low calcium retention, with low bone capacity to

buffer calcium and with an inability to handle an extra calcium

load (31).

The decrease in alkaline phosphatase in the late period is in

accordance with the decrease in bone turnover associated with

the decrease in PTH (3 1). These data suggest that excessive

PTH reduction may lead within a few weeks to a state of

adynamic bone, decreasing the tolerability of a calcium load

that had been adequately handled when P11-I levels were

higher. Because intermittent vitamin D therapy reduces serum

PTH levels at every iCa concentration (32), increases in iCa

result in a self-perpetuating sequence of events: PTH secretion

is initially directly reduced by 1 ,25-dihydroxycholecalciferol

(33-35), which also increases intestinal calcium absorption;

the resulting increase in iCa further suppresses PTH secretion,

leading to a more profound decrease in bone turnover and a

higher iCa, thus creating a vicious circle.

Another issue examined in this study was the effect of a low

pulse dose of 1 p�g of alfacalcidol twice weekly on serum PTH,

after response has been obtained. About half of the patients had

an increase in PTH at 6 wk to more than 3 times the upper

normal limit, and all had such an increase at 46 wk. Until

recently, the management of patients after successful medical

treatment of secondary hyperparathyroidism was unclear. The

recommendation not to administer vitamin D3 to patients with

mildly increased serum PTH does not apply to those patients

who had responded to pulse therapy. Conventional treatment

with daily vitamin D is usually ineffective in controlling PTH

secretion after a successful calcitriol pulse therapy (2 1). Llach

et al. have recently reported (36) that PTH is maintained at

adequate levels when IV calcitriol is administered at a mean

dose of 1 .2 �g three times weekly, after an initial response has

been obtained. A decrease in the maintenance dosage resulted

in a rapid increase in PTH. From the present study, it appears

that an oral alfacalcidol pulse dose of 1 �tg twice weekly is

insufficient in the long term. Because vitamin D3 metabolite

serum concentrations are lower after oral than after intravenous

administration (4), our findings are in accordance with those

reported by Llach et a!. (36). A possible solution would be to

administer a maintenance dose greater than 1 �g twice weekly,

with the potential hazard of decreasing serum PTH to made-

quately low values. An alternative approach would be to mea-

sure serum PTH frequently and to increase alfacalcidol dosage,

as soon as serum PTH increases above target levels.

This study shows that: (1) reducing serum PTH is a major

pathogenic factor, causing hypercalcemia within a few weeks

during pulse therapy with alfacalcidol; (2) lowering dialysate

calcium to 1.0 mmollL is insufficient in preventing hypercal-

cemia; and (3) a maintenance treatment with a relatively low

dose of alfacalcidol does not prevent increases in serum PTH

after successful oral pulse therapy.

AcknowledgmentsWe thank Hadassa Madar, RN, Tova Markowitz, RN, and Rina

Fedorowsky, RN, for their invaluable efforts in performing this study.We also thank Dr. Joseph Levi for his help in initiating this study. The

study was supported by a grant from Teva Medical (Travenol Labs),

Ashdod, Israel.

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