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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.
References1 . Sherrard DI, Hercz 0, Pei Y, Maloney NA, Greenwood C,
Manuel A, Saiphoo C, Fenton 55. Segre GV: The spectrum of
bone disease in end stage renal failure: An evolving disorder.Kidney mt 43: 436-442, 1993
2. Delmez IA, Slatopolsky E, Martin KJ, Gearing BN, Harter HR:Minerals, vitamin D and parathyroid hormone in continuous
ambulatory peritoneal dialysis. Kidney I,it 21: 862-867, 19823. Coburn JW, Salusky lB. Norris KC, Goodman WG: Oral and
parenteral calcitriol for the management of end stage renal dis-
ease. Contrib Nephrol 90: 166-182, 1991
4. Slatopolsky E, Weerts C, Thielan J, Horst RL, Harter H, MartinK!: Marked suppression of secondary hyperparathyroidism byintravenous administration of I ,25-dihydroxycholecalciferol in
uremic patients. J Clin invest 74: 2136-2143, 1984
5. Delmez IA, Tindira C, Grooms P. Dusso A, Windus DW, Sla-
topolsky E: Parathyroid hormone suppression by intravenous
1,25-dihydroxyvitamin D: A role for increased sensitivity to
calcium. J Clin invest 83: 1349-1355. 19896. Andress DL, Norris KC, Coburn IN, Slatopolsky EA, Sherrard
DI: Intravenous calcitriol in the treatment of refractory osteitis
fibrosa of chronic renal failure. N Engl J Med 321 : 274-279,I 989
7. Fugakawa M, Kitaoka M, Kaname 5, Okazaki R, Matsumoto T,Ogata E, Hoshino M, Inada T, Sekine T, Kurokawa K: Suppres-sion of parathyroid gland: Hyperplasia by l,25(OH)2D3 pulse
therapy. N EngI J Med 315: 421-422, 1990
8. Tsukamoto Y, Nomura M, Takayashi Y, Takagi Y, Yoshida A,Nagaoka T, Togashi K, Kikawada R, Marumo F: The oral
1 ,25-dihydroxyvitamin D3 pulse therapy in hemodialysis pa-
1586 Journal of the American Society of Nephrology
tients with severe secondary hyperparathyroidism. Nephron 57:
23-28, 1991
9. Kwan JT, Almond MK, Beer IC, Noonan K, Evans SI, Cunning-ham I: Pulse oral calcitriol in uraemic patients: Rapid modifica-
tion of parathyroid response to calcium. Nephrol Dial Transplant
7: 829-834, 1992
10. Perez-Mijares R, Gomez-Fernandez P, Almaraz-Jimenez M,Ramos-Diaz M, Rivero-Bohorquez I: Treatment of severe sec-
ondary hyperparathyroidism with administration of calcium car-
bonate, intermittent high oral doses of 1,25-dihydroxyvitamin D3
and dialysate with 3 mEqfL calcium concentration. Am J Nephrol
14: 421-425, 1993
1 1 . Tsukamoto Y, Mariyo R, Nomura Y, Sato N, Faugere MC,
Malluche HH: Long term effect oforal calcitriol pulse therapy on
bone in hemodialysis patients. Bone (Elmsford) 14: 421-425,
199312. Quarles LD, Yohay DA, Caroll BA, Spritzer CE, Minda SA,
Bartholomay D, Lobaugh BA: Prospective trial of pulse oralversus intravenous calcitriol treatment of hyperparathyroidism in
ESRD. Kidney mt 45: 1710-1721, 1994
13. Shoji 5, Nishizawa Y, Tabata T, Emoto M, Morita A, Goto H,
Ishimaura E, Inove T, Inaba M, Mike T: Influence of serum
phosphate on the efficacy of oral 1 ,25-dihydroxyvitamin D3
pulse therapy. Miner Electrolyte Metab 21: 223-228, 1995
14. Martin KL, Bullal HS, Domojo DT, Blalock 5, Weindel M: Pulse
oral calcitriol for the treatment of hyperparathyroidism in pa-tients on CAPD: Preliminary observations. Am J Kidney Dis 19:540-545, 1992
15. Hutchison Al, Gokal R: Vitamin D therapy in CAPD: What is its
role? Adv Pent Dial 9: 253-256, 1993
16. Bechtel U, Mucke C, Feucht HE, Schiffi H, Sitter T, Held E:Limitations of pulse oral calcitriol therapy in CAPD dialysis
patients. Am J Kidney Dis 25: 291-296, 1995
17. Malberti F, Scanziani R, Corradi B, Dozio B, Bonforte G, Im-
basciati E, Surian M: High dose oral calcitriol and zero calcium
peritoneal solutions in CAPD patients with refractory second
hyperparathyroidism. Nephrol Dial Transplant 9: 18 13-1815,
I 994
18. Armstrong A, Cunningham I: The treatment of metabolic bone
disease in patients on peritoneal dialysis. Kidney mt 46[Suppl
48]: 551-557, 1994
19. Slatopolsky E, Berkoben M, Kelber I, Brown A, Delmez I:
Effects of calcitriol and noncalcemic vitamin D analogs on
secondary hyperparathyroidism. Kidney mt 42[Suppl 38]: 543-
549, 1992
20. Hutchison Al, Gokal R: Towards tailored dialysis fluids in
CAPD: The role of reduced calcium and magnesium in dialysisfluids. Pent Dial tnt 12: 199-203, 1992
21 . Fukagawa M, Kitaoka M, Yi H, Fukuda N, Matsumoto T, Ogata
E, Kurokawa K: Serial evaluation of parathyroid size by ultra-sonography is another useful marker for the long-term prognosis
of calcitriol pulse therapy in chronic dialysis patients. Nephron
68: 221-228, 1994
22. Andress DL: Blood aluminum in renal osteodystrophy. In:Primer on Metabolic Bone Disease and Disorders of Mineral
Metabolism, edited by Favus Ml, Kelseyville, CA, The Amen-
can Society for Bone and Mineral Research, 1990, pp 76-78
23. Reinhardt TA, Horst PJ, Orf 1W, Hollis BW: A micnoassay for
1,25-dihydroxyvitamin D not requiring high performance liquid
chromatography: Application to clinical studies. J Clin Endocri-
nol Metab 58: 91-98, 1984
24. Cobum 1W: Mineral metabolism and renal bone disease: Effectsof CAPD versus hemodialysis. Kidney mt 43[Suppl 40]: 592-
5100, 199325. Delmez IA, Slatopolsky E: Hyperphosphatemia: Its consequence
and treatment in patients with chronic renal failure. Am J Kidney
Dis 19: 303-317, 1992
26. Naveh-Many T, Rahaminov R, Livni N, Silver I: Parathyroid cell
proliferation in normal and chronic renal failure rats. J Clin
invest 96: 1786-1793, 1995
27. Argiles A, Kerr PG. Canaud B, Flavier IC, Mion C: Calcium
kinetics and the long term effects of lowering dialysate calcium
concentration. Kidney mt 43: 630-640, 1993
28. Cunningham I, Beer I, Coldwell RD, Noonan K, Sawyer N,
Makin HLJ: Dialysate calcium reduction in CAPD patients
treated with calcium carbonate and alfacalcidol. Nephrol Dial
Transplant 7: 63-68, 1992
29. Hercz G, Pei Y, Greenwood C, Manuel A, Saiphoo C, GoodmanWG, Segre GV, Fetton 5, Sherrard DI: Aplastic osteodystrophywithout aluminum: The role of suppressed parathyroid function.
Kidney mt 44: 860-866, 1993
30. Goodman WG, Ramirez IA, Belin TR, Chon Y, Gales B, Segre
GV, Salusky IB: Development of adynamic hypenparathyroidism
after intermittent calcitriol therapy. Kidney mt 46: 1 160-1 166,
1994
31. Kurz P, Monier-Faugere MC, Bognar B, Werner E, Roth P,
Vlachojannis I, Malluche HH: Evidence for abnormal calcium
homeostasis in patients with adynamic bone disease. Kidney fin
46: 855-861, 1994
32. Felsenfeld Al, Llach F: Parathyroid gland function in chronic
renal failure. Kidney mt 43: 771-789, 1993
33. Silver I, Russell I, Sherwood LM: Regulation by vitamin Dmetabolites of messenger RNA for pre-proparathynoid hormone
in isolated bovine parathyroid cells. Proc Nail Acad Sci USA 82:
4270-4273, 1985
34. Cantley LK, Russell I, Lettieri D, Sherwood LM: l,25-dihy-
droxyvitamin D3 suppresses parathyroid hormone secretion from
parathyroid cells in tissue culture. Endocrinology 1 17: 21 14-
2119, 1985
35. Chan YL, McKay C, Dye E, Slatopolsky E: The effect of1 ,25-dihydroxycholecalciferol on parathyroid hormone secretion
by monolayer cultures of bovine parathyroid cells. Calcif Tissue
mt 38: 27-32, 1986
36. LLach F, Hervas I, Cerezo 5: The importance of dosing intra-
venous calcitriol in dialysis patients with severe hyperparathy-
roidism. Am J Kidney Dis 26: 845-851, 1995