Full text of DOI:10.1053/ajkd.2001.27697

A Placebo-Controlled Trial to Evaluate Immunomodulatory
Effects of Paricalcitol
Sharon M. Moe, MD, Mindaugas Zekonis, MD, Jaroslaw Harezlak, MS, Walter T. Ambrosius, PhD,
Christine M. Gassensmith, RN, CCRC, Cynthia L. Murphy, RN, CCRC,
Regina R. Russell, RN, MSN, RNC, and Thomas D. Batiuk, MD, PhD
● Calcitriol has shown a benefit in various small uncontrolled studies of ex vivo immune function. We hypothesized
that paricalcitol, a new vitamin D derivative, will have a positive effect on the immune system with minimal adverse
effects on calcium homeostasis. Thirty-one hemodialysis patients not administered vitamin D because of low intact
parathyroid hormone (PTH) levels were randomized to placebo or 4 ␮g of paricalcitol intravenously with the
hemodialysis session three times weekly for 12 weeks. Effects on in vivo and ex vivo assessments of immune
function were evaluated. All patients achieved the target dose of paricalcitol. Twenty patients were anergic at the
start of the study; 4 of 11 patients in the paricalcitol group and 0 of 9 patients in the placebo group converted to
reactive (P ؍ 0.09). The in vivo response to standard hepatitis B booster vaccine and in vitro proliferation and
release of interleukin-2 (IL-2), IL-6, tumor necrosis factor-␣, and interferon-␥ from stimulated lymphocytes were not
different between the groups. In contrast to clinical immune effects, paricalcitol increased serum calcium levels and
decreased PTH and bone alkaline phosphatase levels (all P < 0.05). However, hypercalcemia was infrequent. In vitro
experiments showed that paricalcitol led to greater dose-dependent thymidine uptake than calcitriol in lymphocytes
isolated from either dialysis patients or control subjects. Paricalcitol has a tendency toward improving delayed
hypersensitivity reactions, but did not have other proimmune effects. However, as expected, paricalcitol had
significant effects on calcium homeostasis compared with placebo. Thus, patients with low PTH levels are unlikely
to experience the proimmune effects of vitamin D therapy without more profound and potentially adverse
oversuppression of PTH.
© 2001 by the National Kidney Foundation, Inc.
INDEX WORDS: Dialysis; immune system; calcitriol; paricalcitol; anergic; hemodialysis.
ALCITRIOL (1,25(OH)2D3) is the active
metabolite of vitamin D, converted from
and the vitamin D response element is found on
many genes outside the skeletal system.1,2 Both
in vivo and in vitro studies have shown a role of
calcitriol in skin disorders, central nervous sys-
tem function, extraskeletal endocrine abnormali-
ties, and immune function.1,2 In vitro studies
evaluating immune function have shown that
calcitriol is important in cell growth and differen-
tiation of T and B lymphocytes, cytokine release
from lymphocytes, macrophage function, and
polymorphonuclear cell chemotaxis.3,4 Effects of
calcitriol in ex vivo and in vivo studies are less
consistent, especially in patients with end-stage
renal disease (ESRD).5 For example, peripheral-
blood mononuclear cells (PBMCs) from patients
with ESRD treated with calcitriol therapy have
improved natural killer cell cytotoxicity6,7 and
altered PBMC response to antigen and mito-
gens.8-10 However, another study was unable to
duplicate these results.11 Of note, none of these
studies had a placebo control group of untreated
patients with ESRD or measured clinical out-
comes. Thus, the role of calcitriol in immuno-
modulation in patients with renal failure is not
clear.
C
25(OH)2D3 by the kidney through the action of
the 1␣-hydroxylase enzyme. Calcitriol is the
most abundant of vitamin D metabolites, with
downstream effects mediated by binding to the
vitamin D receptor (VDR). Traditionally, the
hormone calcitriol has been believed to be impor-
tant only in calcium, phosphorus, and skeletal
homeostasis. However, recent advances indicate
that the VDR is localized to nearly every tissue,
From the Department of Medicine, Divisions of Nephrol-
ogy and Biostatistics, Indiana University School of Medi-
cine; and the Department of Medicine, Richard Roudebush
Veterans Affairs Medical Center, Indianapolis, IN.
Received October 24, 2000; accepted in revised form May
18, 2001.
Supported in part by a grant from Abbott Laboratories
Inc; grant no. DK02775-01 from the National Institutes of
Health (S.M.M.); and a National Kidney Foundation Clini-
cian-Scientist Award (T.D.B.).
Address reprint requests to Sharon M. Moe, MD, Indiana
University School of Medicine, Wishard Memorial Hospital,
1001 W 10th St, OPW 526, Indianapolis, IN 46202. E-mail:
smoe@iupui.edu
© 2001 by the National Kidney Foundation, Inc.
0272-6386/01/3804-0009$35.00/0
All patients with ESRD are deficient in calci-
triol because of the lack of 1␣-hydroxylase in the
doi:10.1053/ajkd.2001.27697
792
American Journal of Kidney Diseases, Vol 38, No 4 (October), 2001: pp 792-802

IMMUNOMODULATORY EFFECTS OF PARICALCITOL
793
failed kidney and decreased calcidiol caused by
poor dietary habits and lack of sunlight expo-
sure.12 This frequently leads to the development
of secondary hyperparathyroidism, treated with
calcitriol supplementation. Most dialysis units
follow a protocol that uses intravenous calcitriol
to suppress parathyroid hormone (PTH) to a
target level of 200 pg/mL.13,14 After patients
achieve that level of PTH, calcitriol dose is
reduced or completely stopped. Typically, calci-
triol dose is also reduced or held if the calcium ϫ
phosphorus product exceeds 70 mg2/dL2. Re-
cently, there has been a trend toward an increas-
ing number of dialysis patients with low PTH
levels, with the majority corresponding to ady-
namic bone on bone biopsy.13 In the US Renal
Data System Dialysis Morbidity and Mortality
(Wave 2) study, 57% of hemodialysis and 67% of
peritoneal dialysis patients were not adminis-
tered vitamin D supplements,15 presumably be-
cause of low PTH levels and/or elevated cal-
cium ϫ phosphorus products. In our own ESRD
population at Indiana University (Indianapolis,
IN), 47% of hemodialysis patients were not
treated with calcitriol, 16% because of high se-
rum calcium and phosphorus levels, and 31%
because of low PTH levels (Moe S, unpublished
observation).
This approach of withholding vitamin D when
PTH levels are suppressed, although presumably
protecting bone, ignores the possibility that cal-
citriol is a hormone with activities beyond bone
and calcium metabolism. This raises the question
of whether all dialysis patients should be on
vitamin D therapy even when not needed for
optimal skeletal function. The potential enhance-
ment of the immune system with calcitriol is
particularly attractive because dialysis patients
are known to be immunosuppressed, and infec-
tions account for 15.5% of all deaths in patients
with ESRD.16 Recently, a new derivative of cal-
citriol, paricalcitol (19-nor-1,25-(OH)2D2; Zem-
plar; Abbott Laboratories, Abbott Park, IL), was
developed, with noticeably less hypercalcemia
and hyperphosphatemia.17 Therefore, it may be
possible to administer paricalcitol to dialysis
patients with low PTH levels to improve immune
function, but without hypercalcemia and hyper-
phosphatemia.
system parameters in hemodialysis patients with
low PTH levels who are otherwise not on vita-
min D therapy. The safety of this potential immu-
nomodulating therapy was also evaluated.
METHODS
Study Design
The study was a 12-week, randomized, placebo-con-
trolled, double-blind study comparing placebo with parical-
citol administered intravenously thrice weekly in hemodialy-
sis patients. The primary end point was improvement in
patient immune function in the paricalcitol group, assessed
by: (1) ex vivo tests of PBMC cytokine production in
response to known stimulators, (2) ex vivo tests of PBMC
antigen-specific proliferation (mixed lymphocyte reaction
[MLR]), (3) in vivo tests of delayed hypersensitivity (T-cell
function) by conversion from anergic (nonreactive) to reac-
tive using standard skin inoculation tests, and (4) in vivo
tests of B-cell function by measuring the change in antibody
titer before and after hepatitis B booster vaccine. Secondary
end points were the number of hypercalcemic events and
changes in serum calcium, phosphorus, calcium ϫ phospho-
rus product, PTH, and total and bone alkaline phosphatase
values over the course of the study. Other analyses included
the number of times patients were prescribed antibiotics and
number of visits in which patients required the administra-
tion of sevelamer (Renagel; Genzyme Therapeutics, Waltham,
MA) as a phosphate binder to control hypercalcemia.
Patients were recruited from three area dialysis units and
were eligible if they met the following inclusion and exclu-
sion criteria. Inclusion criteria were: (1) age older than 18
years, (2) on hemodialysis therapy for at least 3 months, (3)
able to give informed consent, (4) medically stable, (5)
serum intact PTH level less than 200 pg/mL, (6) not on
calcitriol or other vitamin D therapy for at least 3 months, (7)
serum calcium level (corrected for albumin level of 4.0
mg/dL) less than 10.5 mg/dL in 80% of measurements in the
last 6 months or last three consecutive measurements ob-
tained during a 2-week period after reducing the patient’s
dialysis bath calcium concentration or last three consecutive
measurements obtained during a 2-week period after chang-
ing a patient from a calcium-containing phosphate binder to
sevelamer during the run-in portion of the protocol, (8)
serum phosphorus level greater than 2.5 and less than 7.0
mg/dL in 80% of measurements in the last 6 months or a
calcium ϫ phosphorus product of 70 mg2/dL2 or less in 80%
of measurements in the last 6 months, (9) serum 1,25(OH)2D3
levels less than normal range, and (10) hematocrit greater
than 30%. Exclusion criteria were: (1) known active malig-
nancy; (2) liver disease defined as serum aspartate amino-
transferase, alanine aminotransferase, or ␥-glutamyltrans-
ferase levels greater than two times the upper limits of
normal; (3) human immunodeficiency virus or other known
immune system disorder; (4) history of more than 1 month
of therapy with the daily ingestion of 90 mL or 3 tabs of
aluminum hydroxide by history or chart review or an el-
evated aluminum level greater than 40 ␮g/L; (5) pregnant or
lactating women; or (6) currently administered drugs known
to suppress immune function, such as corticosteroids. The
The present study tested the hypothesis that
paricalcitol has a positive effect on immune

794
MOE ET AL
protocol was approved by the Indiana University-Purdue
University at Indianapolis Institutional Review Board, and
informed consent was obtained for all patients.
PBMCs in 0.2 mL of medium in sterile 96-well plates for 96
hours. Stimulator cells from a random third-party healthy
donor were irradiated with 2,000 rads before addition to
culture. The same donor was used throughout the study.
Sixteen hours before harvesting, 2 mCi of 3H-thymidine was
added to each well. Cells were harvested, washed, counted,
and added to scintillation vials. Four milliliters of scintilla-
tion fluid was added, and CPM (counts per minute) counted.
Proliferation of PBMCs in response to mitogen was deter-
mined using 5 ϫ 104 patient PBMCs incubated in 0.2 mL
with 1 ␮g/mL of phytohemagglutinin (PHA; Sigma, St
Louis, MO) for 96 hours, and 3H-thymidne uptake was
measured as described. For both antigen-dependent and
mitogen-dependent proliferation, the effect of each stimulus
is reported as the ratio of CPM in the stimulus group to CPM
in the unstimulated control group. Ratios of results for CPM
values obtained at follow-up to baseline were determined for
each patient.
Cytokine production in response to soluble stimuli. In
separate experiments, freshly isolated PBMCs were incu-
bated at 1 ϫ 106/well overnight with one of the following:
(1) 5 ␮mol/L of the calcium ionophore ionomycin (Calbio-
chem, La Jolla, CA) plus 15 ng/mL of phorbol 12 myristate
13-acetate (PMA) (Sigma), (2) 2 ␮g/mL of PHA, or (3)
1:100 dilution of anti-CD3 activating antibody (clone
UCHT1; Calbiochem). Supernatants from cultures were
collected, frozen at –70°C, and assayed as paired samples
(baseline and follow-up). Levels of interleukin-6 (IL-6),
IL-2, tumor necrosis factor-␣ (TNF-␣), and interferon-␥
(INF-␥) were measured by enzyme-linked immunosorbent
assay (ELISA; PeliKine Compact ELISAkit; Research Diag-
nostics Inc, Flanders, NJ). All assays were corrected for
control values obtained from cells incubated in the absence
of stimulators. The stimulated value was divided by control
value to determine the proportion attributable to stimulation
at both baseline and follow-up (stimulation index). Next, the
follow-up index was divided by baseline index, and the
logarithm of the ratio was taken. For IFN-␥, results were not
divided by the baseline index because control values were
zero or near zero.
Tests of delayed hypersensitivity response. Patients un-
derwent testing by application of an anergy panel at baseline
and after 12 weeks of therapy. The anergy panel consisted of
intradermal injections of 0.1 mL of purified protein deriva-
tive (PPD; 5 U/0.1 mL), mumps (10 U/0.1 mL), Candida (40
U/0.1 mL), and trychophytin (20 U/0.1 mL) applied to the
forearm of the nonaccess arm and read at 48 hours. Patients
were considered anergic if the resultant induration in all four
tests was less than 10 mm in diameter each. Patients were
considered reactive if the resultant induration in any of the
four tests was 10 mm or greater in diameter.
Response to hepatitis vaccine. Patients had a quantita-
tive hepatitis B surface antigen level determined after 8
weeks of therapy, followed by the administration of 10 mg
of recombinant hepatitis B vaccine (Engerix-B; SmithKline
Beecham, Philadelphia, PA). The titer was repeated 4 weeks
later (which corresponds to peak antibody titer response) at
the conclusion (follow-up visit) of the study. Sera for both
determinations were frozen at –70°C and both preadministra-
tion and postadministration results were assayed simulta-
neously by ELISA (Specialty Labs, Santa Monica, CA).
Patients underwent a 2- to 3-week run-in period in which
they were changed to a low-calcium dialysate or sevelamer
(provided by GelTex Pharmaceuticals, Waltham, MA) if
serum calcium level corrected for albumin level was greater
than 10.5 mg/dL. After serum calcium levels were stable,
defined in the inclusion criteria, patients were randomized
1:1 to the administration of paricalcitol or placebo of the
same base solution (supplied by Abbott Laboratories) after
stratification of patients with diabetes administered insulin
because of a potential interaction of calcitriol and insulin.18
The initial dose of paricalcitol or placebo was 0.20 mL (1 ␮g
of paricalcitol). Serum calcium and phosphorus levels were
monitored twice each week. Dose was increased by 0.20 mL
each week to a maximum of 0.8 mL (equivalent to 4 ␮g of
paricalcitol) providing the corrected calcium level was less
than 11.5 mg/dL and calcium ϫ phosphorus product was
less than 75 mg2/dL2. All patients reached the target dose by
week 4.
After patients reached the target dose, serum calcium and
phosphorus levels were checked twice weekly. Calcium
level was corrected based on the serum albumin level
measured that calendar month as part of routine dialysis
laboratory workup. For safety purposes, if the corrected
calcium level was greater than 11.5 mg/dL or calcium ϫ
phosphorus product was greater than 75 mg2/dL2, the cal-
cium bath was decreased to 2 mEq/L and/or the patient was
converted to sevelamer as a phosphate binder. If this failed
to bring the calcium level or calcium ϫ phosphorus product
into the safety limits by two dialysis sessions or patients
were already administered sevelamer and a 2-mEql/L cal-
cium bath, the dose of paricalcitol was decreased by 0.2 mL
(1 ␮g), and calcium and phosphorus measurements were
repeated. If this failed to bring the calcium level or product
into the safety limits (11.5 mg/dL and 75 mg2/dL2, respec-
tively), the dose of paricalcitol was decreased again by 0.2
mL (1 ␮g) every third dialysis session. A patient unable to
tolerate any dose of paricalcitol was removed from the study.
Thus, the maximum dose of paricalcitol at which the cal-
cium level is less than 11.5 mg/dL and calcium ϫ phospho-
rus product is 75 mg2/dL2 was used, up to 4 ␮g per dialysis
treatment. This target dose of paricalcitol was chosen to be
equivalent with 1 ␮g of intravenous calcitriol thrice weekly.19
This was similar to doses of intravenous calcitriol showing
positive immunomodulation effects in ex vivo studies of
PBMCs from hemodialysis patients.7,10,11
In Vivo and Ex Vivo Studies
Before starting treatment (baseline) and again after 12
weeks of treatment (36 dialysis sessions; follow-up), the
following studies were performed.
PBMC proliferation. Whole blood (30 mL) was col-
lected in heparinized tubes predialysis from study patients,
and PBMCs were isolated by Ficoll gradient centrifugation.
PBMCs then were stimulated, and proliferation was mea-
sured by uptake of tritium (3H)-thymidine. Antigen-specific
proliferation was tested in a one-way MLR as previously
described.20 Briefly, 0.5 ϫ 104 patient PBMCs were mixed
with 5 ϫ 104 (1:1 ratio) or 10 ϫ 104 (1:2 ratio) stimulator

IMMUNOMODULATORY EFFECTS OF PARICALCITOL
795
Serum chemistry tests. In addition to calcium and phos-
phorus determinations, sera were collected at baseline and at
the completion of the study for measurements of intact PTH,
total alkaline phosphatase, bone alkaline phosphatase, and
complete blood count with complete differential. Calcium,
phosphorus, and alkaline phosphatase were analyzed on a
Vitros 950 Autoanalyzer (Ortho Clinical Diagnostics, Roch-
ester, NY). Intact PTH was measured by ELISA with chemi-
luminescence detection (Nichols Laboratories, San Juan
Capistrano, CA). Bone alkaline phosphatase was determined
by ELISA (Metra Biosystems, Mountain View, CA).
tol groups were of interest, and t-test for the difference in
slopes was used. Random-effects analysis of variance was
used for analysis of thymidine uptake in in vitro experiments
comparing PBMCs isolated from healthy subjects versus
patients with ESRD and between calcitriol and paricalcitol
after adjustment for molar concentration. Fisher’s exact test
was used for comparison of proportions of anergic patients
converting to reactive and responses to hepatitis B booster
vaccine.
RESULTS
Additional data. The number of infections during the
study was recorded and defined as a prescription of antibiot-
ics, regardless of whether positive cultures were obtained.
The number of dialysis sessions (of a possible 36 sessions)
during which patients were administered sevelamer was
recorded as an estimate of requirements for maintaining
serum calcium levels within the desired range. Dialyzer
reuse number was also recorded.
Patient Characteristics
Thirty-two patients entered the study, and two
patients did not complete the study. One patient
randomized to the paricalcitol group was admin-
istered one dose of paricalcitol, then it was
realized that he did not fulfill inclusion criteria
and he was dropped from the study. The second
patient, in the paricalcitol arm, died suddenly of
a presumed myocardial event 2 weeks into the
study. Results of the second patient are included
in the baseline analysis only. A comparison of
demographic and baseline chemistry values is
listed in Table 1 and indicates appropriate ran-
domization. Of note, baseline (visit 1 of actual
study after run-in) PTH level was greater than
values obtained at screening, in part because of
changes in calcium bath and/or change to sevel-
amer therapy during the run-in period. Two pa-
tients previously had undergone parathyroidec-
tomy, both in the placebo group. Duration of
ESRD was similar in both groups. In the parical-
citol group, 5 patients had been on dialysis
therapy for less than 1 year; 9 patients, 1 to 5
years; 2 patients, 5 to 10 years, and no patient,
longer than 10 years. For the placebo group, 3
patients had been on dialysis therapy for less
than 1 year; 7 patients, 1 to 5 years; 2 patients, 5
to 10 years; and 3 patients, longer than 10 years.
Causes of ESRD in patients included diabetes
mellitus (7 patients in each group), hypertension
(6 patients, paricalcitol; 7 patients, placebo), and
other miscellaneous causes (3 patients, paricalci-
tol; 1 patient, placebo). Racial distribution was
also similar between groups. In the paricalcitol
group, 9 patients were black; 5 patients, white;
and 2 patients, Hispanic. In the placebo group,
10 patients were black and 5 patients were white.
This racial distribution is similar to our overall
dialysis patient population. No patient was on
initial use of dialyzer at baseline or follow-up
visits.
In Vitro Studies
To determine whether paricalcitol has a similar ability to
inhibit PBMC proliferation in vitro as calcitriol, PBMCs
were isolated as described from three dialysis patients and
three age- and sex-matched healthy donors. Cells were
divided into equal aliquots and stimulated for 96 hours in the
presence of 2 ␮g/mL of PHA in the presence or absence of
10–13 to 10–7 mol/L concentration of either paricalcitol or
3
calcitriol, and H-thymidine uptake was determined as de-
scribed. CPM was normalized for control (no vitamin D)
values.
Statistical Analysis
Comparison between the placebo and paricalcitol groups
was performed for ex vivo lymphocyte function and changes
in PTH, total and bone alkaline phosphatase, and serum
calcium levels over time. Also, comparisons were made
between calcitriol and paricalcitol for effects of in vitro
PBMC proliferation.
Evaluation of ex vivo lymphocyte function was per-
formed incorporating the following procedure: (1) the stimu-
lated value was divided by control value to obtain the
proportion attributable to the stimulant at both baseline and
follow-up (stimulation index), (2) the follow-up stimulation
index was divided by baseline stimulation index, and (3) the
logarithm was obtained of the ratio of stimulation indices.
The only exception to part (1) of the described procedure
was IFN-␥, for which control values were near zero and the
stimulant value was not divided by control value. All descrip-
tive statistics for ex vivo lymphocyte function are on the
logarithmic scale. A two-sample t-test was used to compare
the placebo and paricalcitol groups.
PTH and total and bone alkaline phosphatase levels were
observed at baseline and follow-up. Analysis of covariance
and two-sample t-tests were used for comparison of the
change between the placebo and paricalcitol groups. Serum
calcium was measured over the 12-week period (average, 25
times per subject). A random-effects model with random
subject-specific slope and intercept was used for the analy-
sis. Differences in slopes between the placebo and paricalci-

796
MOE ET AL
Table 1. Baseline Patient Characteristics and
Laboratory Values
four tested antigens. At follow-up, 4 anergic
patients became reactive (all in the paricalcitol
group), and 3 initially reactive patients became
anergic (all in the placebo group). For compari-
son purposes, a clinically positive response was
conversion from anergic to reactive or staying
reactive. A clinically negative response was lack
of conversion from anergic to reactive or convert-
ing from reactive to anergic. For the latter analy-
sis, 8 of 15 patients in the paricalcitol group
compared with 3 of 15 patients in the placebo
group had a clinically positive response (P ϭ
0.13). If only patients who were anergic at base-
line were evaluated, then 4 of 11 patients in the
paricalcitol group converted to reactive, whereas
0 of 9 patients in the placebo group converted
(P ϭ 0.09). The presence or absence of diabetes
did not alter these results.
Placebo
Paricalcitol
(n ϭ 15)
(n ϭ 16)
Age (y)
53.6 Ϯ 11.4
53.0 Ϯ 9.6
Sex (M/F)
No. of patients with
diabetes
8/7
7
12/4
7
Kt/V
1.49 Ϯ 0.26
1.50 Ϯ 0.35
PTH at screening
(pg/mL)
108.4 Ϯ 68.2
117.5 Ϯ 48.1
PTH at baseline*
(pg/mL)
236.3 Ϯ 242.2 190.2 Ϯ 183.0
Calcium corrected for
albumin (mg/dL)
Phosphorus (mg/dL)
Calcium ϫ phosphorus
product
9.1 Ϯ 0.7
9.7 Ϯ 0.9
5.9 Ϯ 1.2
54.3 Ϯ 11.8
5.0 Ϯ 1.7
48.6 Ϯ 17.9
Albumin (g/L)
3.4 Ϯ 0.4
3.4 Ϯ 0.5
Total alkaline
95.3 Ϯ 37.7
93.9 Ϯ 25.7
phosphatase (IU)
Bone alkaline
B-Cell Response
12.3 Ϯ 4.1
11.5 Ϯ 2.9
phosphatase (ng/mL)
White blood cells/mm3
Hemoglobin (g/dL)
Hematocrit (%)
Glucose (mg/dL)
Bicarbonate (mmol/L)
Four patients did not have complete preadmin-
istration (8 weeks) and postadministration (12
weeks) hepatitis B titer values because of inad-
8.7 Ϯ 3.9
11.1 Ϯ 1.1
33.2 Ϯ 3.0
156.1 Ϯ 101.6 115.9 Ϯ 52.7
20.6 Ϯ 3.4 21.2 Ϯ 3.0
8.2 Ϯ 2.1
11.2 Ϯ 1.4
33.8 Ϯ 4.3
Table 2. Ex Vivo Lymphocyte Function
NOTE. Values expressed as mean Ϯ SD.
*After run-in phase.
Assay
IL-6
Placebo
Paricalcitol
P
Io ϩ PMA
PHA
CD3
1.237 Ϯ 3.009
Ϫ0.413 Ϯ 4.196
0.627 Ϯ 3.126
0.461 Ϯ 3.417 0.54
0.582 Ϯ 2.815 0.48
0.22 Ϯ 3.004 0.73
Cytokine Release and MLR
The effect of paricalcitol on cytokine release
by PBMCs simulated ex vivo by three different
stimuli is listed in Table 2. The difference be-
tween follow-up to baseline release of IL-2,
TNF-␣, IL-6, and INF-␥ was not different be-
tween the placebo and paricalcitol groups. Simi-
larly, antigen-specific and mitogen-stimulated
lymphocyte proliferation were not different (Table
2). All analyses of ex vivo lymphocyte function
showed considerable interpatient variability, ex-
emplified by Fig 1, showing IL-2 release from
PBMCs stimulated with PHA in each patient.
The variability is such that we have no reason to
reject the null hypothesis of no difference despite
a sample size that was adequate based on previ-
ous uncontrolled studies.
TNF-␣
Io ϩ PMA
PHA
CD3
1.625 Ϯ 1.823
0.878 Ϯ 2.196
0.445 Ϯ 2.097
1.484 Ϯ 2.872 0.88
0.711 Ϯ 2.882 0.87
0.573 Ϯ 2.289 0.88
IL-2
Io ϩ PMA Ϫ1.973 Ϯ 1.881 Ϫ1.485 Ϯ 1.304 0.43
PHA
CD3
IFN-␥
Io ϩ PMA Ϫ0.320 Ϯ 1.887 Ϫ0.259 Ϯ 1.441 0.92
PHA
CD3
Ϫ1.383 Ϯ 1.310 Ϫ0.550 Ϯ 1.066 0.09
Ϫ0.595 Ϯ 0.796 Ϫ0.034 Ϯ 1.068 0.13
Ϫ0.633 Ϯ 2.380
Ϫ0.585 Ϯ 1.56
0.053 Ϯ 1.387 0.37
0.313 Ϯ 1.483 0.13
MLR
1:1 ratio
1:2 ratio
PHA
0.136 Ϯ 1.366 Ϫ0.010 Ϯ 0.808 0.74
0.067 Ϯ 2.074
Ϫ0.080 Ϯ 2.284
0.248 Ϯ 0.896 0.77
0.305 Ϯ 1.251 0.58
NOTE. See text for description of calculations, which are
presented on a logarithmic scale, as mean Ϯ SD. Thus, if
the ratio is positive, it means levels increased with time,
and if the ratio is negative, it means levels decreased
during the course of the study.
Anergy Testing
On initial testing, 20 of 31 patients were
anergic, similar to previous reports.21 The remain-
ing 11 patients were reactive to at least one of the
Abbreviations: Io, ionomycin; PMA, phorbol 12-myristate
13-acetate.

IMMUNOMODULATORY EFFECTS OF PARICALCITOL
797
Fig 1. PBMCs were iso-
lated from blood collected
from patients undergoing he-
modialysis before and after
12 weeks of treatment with
(left) placebo or (right) pari-
calcitol. PBMCs were stimu-
lated overnight with PHA,
and supernatants were ana-
lyzed for the presence of IL-2
to determine the stimulation
index. The follow-up stimula-
tion index was divided by
baseline stimulation index
and the logarithm taken. This
figure shows the interpatient
variability in the placebo
and paricalcitol treatment
groups.
equate sera for quantification of the preadminis-
tration value (n ϭ 3) or they were in the middle
of their initial three-dose vaccine administration
(n ϭ 1). The number of patients responding to
the hepatitis B booster vaccine (defined as an
increase in titer by 10 U/mL) was not different
between the two groups (6 of 13 patients, parical-
citol; 9 of 13 patients, placebo). The overall
number of patients responding to the vaccine
was low compared with patients without ESRD
and consistent with previous results of poor
response to hepatitis B vaccine in dialysis pa-
tients.22,23
were administered sevelamer at 27 Ϯ 13 patient
visits for the paricalcitol group and 19 Ϯ 17
visits for the placebo group (P ϭ 0.17). Six
patients in the placebo group compared with two
patients in the paricalcitol group were able to
maintain calcium levels in the target range with-
out the use of sevelamer. There was no signifi-
cant change in serum phosphorus levels with
time in either group. The calcium ϫ phosphorus
product also increased more in the paricalcitol
group than placebo group, but the difference was
only marginally significant (P ϭ 0.07). Total
alkaline phosphatase levels were not different
between the two groups (placebo, 95.3 Ϯ 37.7 to
105.3 Ϯ 28.9 IU/L; paricalcitol, 93.9 Ϯ 25.7 to
92.1 Ϯ 23.5 IU/L; P ϭ 0.108). However, bone-
specific alkaline phosphatase levels decreased in
the paricalcitol group (12.3 Ϯ 4.1 to 11.5 Ϯ 2.9
ng/mL) compared with an increase in the pla-
cebo group (12.3 Ϯ 4.0 to 14.1 Ϯ 5.5 ng/mL;
P ϭ 0.038).
Results of Chemistry Tests and Safety
Paricalcitol decreased serum PTH levels sig-
nificantly (190.2 Ϯ 183 to 84.9 Ϯ 95.6 pg/mL)
compared with placebo (236.3 Ϯ 242.2 to
242.5 Ϯ 226.2 pg/mL; P ϭ 0.008). The change
in serum calcium level was greater in the parical-
citol group than placebo group (slope, 0.0072
versus 0.0024; P ϭ 0.003; Fig 2). There were
four hypercalcemic events, defined as a serum
calcium level greater than 11.5 mg/dL, in the
paricalcitol group and two events in the placebo
group (P ϭ not significant). Only two patients in
the paricalcitol group required dose reduction,
both in the last 2 weeks of the study. Patients
Additional Results
Three patients in each group had one infec-
tious episode during the study, and two patients
in each group had two infectious episodes during
the study. One patient was excluded from this
determination because he was administered anti-

798
MOE ET AL
Fig 2. Hemodialysis pa-
tients were treated for 12
weeks with either placebo or
paricalcitol.
A random-ef-
fects model was fit to the
observed levels of serum cal-
cium corrected for albumin
level over the study period.
Estimated changes in serum
calcium levels are shown for
the (left) placebo and (right)
paricalcitol groups. There is
a statistically significant dif-
ference in the slopes of the
two groups (P ؍ 0.003).
biotics for the entire duration of the study for a
diabetic foot ulcer.
quency of malignancies,5 poor response to immu-
nizations,22 and increased infections. Infections
are the second most common cause of death,
after cardiovascular events, and accounted for
15.5% of all deaths in patients with ESRD be-
tween 1992 and 1995.16 In addition, infections
In Vitro 3H-Thymidine Uptake
To determine whether the apparent absence of
immunomodulatory effects of paricalcitol was
caused by a difference in effects of paricalcitol
on PBMCs, we compared thymidine uptake in-
duced by paricalcitol versus calcitriol in PHA-
stimulated PBMCs from three dialysis patients
and three age- and sex-matched healthy controls,
corrected for basal (control media) uptake. As
shown in Fig 3 by random-effects analysis of
variance, paricalcitol induced a greater prolifera-
tion than calcitriol after adjusting for concentra-
tion. There was no difference between patients
and controls. These concentrations were chosen
to reflect peak serum concentrations obtained
after 2 hours of intravenous administration of 1
␮g of calcitriol and 4 ␮g of paricalcitol in a
70-kg person (10–10 mol/L) and at 24 hours after
intravenous administration (10–11 mol/L24 [S. Tu,
PhD, Abbott Laboratories, personal communica-
tion, December 2000]).
Fig 3. To determine whether paricalcitol had a simi-
lar effect on in vitro PBMC proliferation as calcitriol,
thymidine uptake was measured in stimulated PBMCs
from three dialysis patients (ESRD) and three age- and
sex-matched controls (Ctls). Results show greater thy-
midine uptake for both controls and patients with
ESRD for paricalcitol compared with calcitriol when
adjusted for molar concentration (P < 0.002). The
response in control patients was not different from the
response in dialysis patients (P > 0.2).
DISCUSSION
It is widely accepted that uremia is an immu-
nosuppressed state, shown by increased fre-

IMMUNOMODULATORY EFFECTS OF PARICALCITOL
799
cause significant morbidity and are the primary
reason for patients to convert from peritoneal
dialysis to hemodialysis.25 Unfortunately, infec-
tions remain a significant cause of morbidity and
mortality in dialysis patients despite improve-
ments in the treatment of anemia with erythropoi-
etin and improved dialysis clearance of low- and
middle-molecular-weight uremic toxins with
high-flux and more biocompatible dialysis mem-
branes. The cause of this immunosuppressed
state is unclear and likely multifactorial. How-
ever, the importance of this immunodeficient
state is further supported by a recent study by
Kimmel et al26 showing increased survival of
hemodialysis patients with superior T-cell func-
tion.
In the present study, we attempted to duplicate
previously published uncontrolled studies of en-
hanced ex vivo immune function in response to
vitamin D derivatives in patients with ESRD in a
randomized controlled study. However, we were
unable to show a statistically significant improve-
ment in lymphocyte proliferation or secretion of
IL-2, IL-6, TNF-␣, or IFN-␥ from PBMCs. Our
results are in contrast to the study by Tabata et
al,8 who examined 7 patients with ESRD treated
with 0.5 ␮g/d of oral 1␣-OHD3 for 4 weeks and
found increased PBMC proliferative response to
such stimulants as PHA. Riancho et al9 treated 7
patients with 0.5 ␮g/d of calcitriol for 1 month
and found increased IL-1 and IL-6 release, but
decreased TNF-␣ release from stimulated
PBMCs. Similar to our study, Antonen et al11
found that 1 to 1.5 ␮g of intravenous calcitriol
for 2 months in 10 hemodialysis patients did not
increase the proliferation of stimulated lympho-
cytes. However, a subanalysis by Antonen et al11
found that stimulating PBMCs with PPD from
patients with documented calcitriol deficiency
enhanced proliferation. In the present study, cal-
citriol deficiency was an inclusion criterion; how-
ever, we still did not observe enhanced PBMC
proliferation. All these previous studies com-
pared effects of vitamin D derivatives within an
individual patient over time, but did not include a
placebo group and were smaller than the present
study. Thus, our study is the first randomized
placebo-controlled trial. This is particularly im-
portant when one notes the interpatient variabil-
ity observed in the placebo arm for many param-
eters tested, indicating that multiple other factors
influence ex vivo lymphocyte function.
The relevance of in vitro or ex vivo lympho-
cyte function to clinical parameters of immune
function is not entirely proven, especially in the
dialysis patient population. Although Kimmel et
al26 found that the proliferation of PBMCs stimu-
lated with PPD, streptolysin, Candida, and teta-
nus toxoid positively correlated with increased
survival, multiple other factors, including albu-
min level, protein catabolic rate, and indices of
comorbid conditions, also were strongly associ-
ated with survival. Furthermore, this study did
not evaluate the role of vitamin D administration.
Thus, it is unclear whether the greater prolifera-
tion index was caused by a specific intervention
or, more likely, indicative of better overall health.
We also sought to determine whether paricalcitol
had a positive effect on in vivo assays of immune
function, although these tests are only crude
indicators given the complexity of the immune
response. There was a favorable trend toward
enhanced delayed hypersensitivity response, as-
sessed by skin anergy panel testing, because all
patients who converted from nonreactive to reac-
tive were in the paricalcitol group. It is possible
that this difference would have been statistically
significant had our study been larger because
sample size calculations using these results indi-
cate 44 patients in each arm would be required.
However, further studies are needed to determine
whether a change in delayed hypersensitivity
would translate to a clinically important effect on
infection rates or severity.
Humoral responsiveness is also impaired in
ESRD. Studies evaluating the antibody response
to hepatitis B vaccine found that 15% to 40% of
patients with chronic renal failure and ESRD
failed to achieve optimal titers to confer protec-
tion.27,28 Because of this, the Centers for Disease
Control and Prevention (CDC) Immunization
Practices Advisory Committee recommends an-
nual measurement of hepatitis B antibody levels
and booster vaccines in all patients with ESRD
who have suboptimal titers (Ͻ10 mIU/mL).23
The reason for the poor response to hepatitis B
vaccine in patients with ESRD is unknown. We
found no effect of paricalcitol on response to
booster doses of hepatitis vaccine, similar to the
results of Peces et al,27 who found no effect of
calcitriol on the response to the initial full-series

800
MOE ET AL
hepatitis B vaccine. Girndt et al22 found in-
creased production of IL-6 and TNF-␣ and de-
creased production of IL-10 from PBMCs stimu-
lated with lipopolysaccharide in patients who did
not respond compared with those who responded
to the vaccine. However, we found no relation-
ship with those levels in patients who did and did
not respond. Altun et al29 also found no effect of
calcitriol on the B-cell activation marker CD23.
Based on our data, it is unclear that the CDC
recommendations are cost effective.
tients, there was a significant effect on PTH,
calcium, and bone alkaline phosphatase levels.
The purpose of this study is to determine whether
paricalcitol could be safely administered to pa-
tients not on vitamin D therapy for control of
secondary hyperparathyroidism. The reason pa-
tients chosen for the present study (PTH Ͻ 200
pg/mL) were not on therapy with vitamin D was
in part because of concern for hypercalcemia
and/or hyperphosphatemia and the possibility of
oversuppression of PTH. Oversuppression of
PTH may lead to the development of adynamic
bone, which is increasing in prevalence.13,14,35-37
Long-term sequelae of adynamic bone disease
are unknown, but these patients are at risk for
fractures38 and hypercalcemia, in part because of
an inability of adynamic bone to buffer an acute
calcium load.39 Our choice of paricalcitol as an
immune-modulating vitamin D derivative was to
avoid hypercalcemia. We chose a dose of parical-
citol to be equivalent to calcitriol from a PTH
and, presumably, bone effect. Compared with
other studies that used calcitriol, we saw similar
PTH suppression,7,9-11 but less hypercalcemia.
Whether the suppression of PTH observed in
response to either paricalcitol or calcitriol would
lead to or worsen adynamic bone would require a
longer treatment time and serial bone biopsies.
However, based on biochemical results, it ap-
pears from the present study that potential ad-
verse consequences on PTH and calcium ho-
meostasis outweigh potential immunomodulatory
benefits. Given the potential adverse conse-
quences of adynamic bone and hypercalcemia,
immunomodulatory effects would need to be
dramatic to warrant such therapy in patients with
low PTH levels. However, it is possible that
lower doses of paricalcitol administered for a
longer time or on a daily basis may lead to fewer
adverse sequelae on calcium homeostasis, but a
positive immunomodulatory effect. However, the
dose of paricalcitol in this study was chosen to
approximate previous studies showing positive
immunomodulatory effects; therefore, the poten-
tial immunomodulatory effect of lower doses of
paricalcitol would need to be proven.
There are several reasons why we may have
failed to show a positive effect of paricalcitol on
immune function. First, it is possible that parical-
citol has less of an effect than calcitriol on
immune function in vivo and ex vivo. Paricalci-
tol was designed to have a predominant effect at
the parathyroid gland, and the mechanism for its
decreased hypercalcemic and hyperphosphatemic
effects is unknown.30 Considering the concentra-
tion of paricalcitol used in this study, the relative
lack of hypercalcemic events was impressive.
However, our in vitro studies showed a greater in
vitro effect of paricalcitol compared with calci-
triol in PBMC proliferation in both patients with
ESRD and healthy controls, so this is not a likely
explanation for the negative results. However, a
randomized trial comparing paricalcitol with cal-
citriol and placebo would be required to confirm
the applicability of these results to in vivo. Sec-
ond, the presence of other potential confounding
variables was not fully evaluated in this study.
PTH levels,31 purine metabolites,32 urea concen-
tration, acidosis,33 and type of dialysis34 have
been shown to influence immune response in
uremia. These other factors may also explain
why in vitro data for PBMCs incubated with
calcitriol showed more uniform positive immuno-
modulation. Although the randomized nature of
this study should lead to fairly equivalent comor-
bidities between the two groups, the sample size
precludes complete evaluation of these confound-
ers. Third, although the sample size for this study
was larger than previously published studies of
ex vivo PBMC response to calcitriol,7,9-11 this
study had a relatively small sample size. How-
ever, there was not even a sufficient trend of
proimmune effects to use for estimation of sample
size for a larger study, with the exception of the
effects on anergy.
In conclusion, results of this study indicate
that the potential immunoprotective effects of
paricalcitol (and probably all forms of vitamin
D) therapy in patients not otherwise on vitamin
D therapy cannot be achieved without signifi-
However, despite the small number of pa-

IMMUNOMODULATORY EFFECTS OF PARICALCITOL
801
9. Riancho JA, Zarrabeitia MT, de Francisco AL, Amado
JA, Napal J, Arias M, Gonzalez-Macias J: Vitamin D therapy
modulates cytokine secretion in patients with renal failure.
Nephron 65:364-368, 1993
10. Panichi V, De Pietro S, Andreini B, Bianchi AM,
Migliori M, Taccola D, Giovannini L, Tetta C, Palla R:
Calcitriol modulates in vivo and in vitro cytokine produc-
tion: A role for intracellular calcium. Kidney Int 54:1463-
1469, 1998
11. Antonen J, Saha H, Lagerstedt A, Krohn K, Paster-
nack A: Intravenous calcitriol therapy restores reduced anti-
gen-induced T-lymphocyte response in 1,25-(OH)2D3-
deficient hemodialysis patients. Nephron 74:680-686, 1996
12. Fournier A, Fardellone P, Achard JM, Ghazali A,
Pruna A, El Esper N, Moriniere P: Importance of vitamin D
repletion in uraemia. Nephrol Dial Transplant 14:819-823,
1999
13. Sherrard DJ, Hercz G, Pei Y, Maloney NA, Green-
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cantly suppressing PTH levels and bone alkaline
phosphatase and increasing serum calcium lev-
els. The variability in responses observed on this
study indicate that any potential immunomodula-
tory effect of vitamin D in dialysis patients is
masked by many other factors. That said, should
we be alarmed that many of our dialysis patients
are deficient in the essential vitamin (or hor-
mone) D? This may be answered by the VDR
knockout mouse in which secondary hyperpara-
thyroidism, bone rickets, and alopecia are the
only abnormalities noted and survival is unaf-
fected.40 Furthermore, in patients with many dif-
ferent types of rickets, skeletal growth is ad-
versely affected, but without obvious clinically
significant immune deficits.41 Thus, at the present
time, in patients not on vitamin D therapy for the
treatment of secondary hyperparathyroidism,
widespread use of vitamin D supplements for
potential immunomodulatory effects cannot be
recommended.
15. US Renal Data System: USRDS 1997 Annual Data
Report. The National Institutes of Health, National Institute
of Diabetes and Digestive and Kidney Diseases, Bethesda,
MD, 1997
16. US Renal Data System: USRDS 1997 Annual Data
Report. The National Institutes of Health, National Institute
of Diabetes and Digestive and Kidney Diseases, Bethesda,
MD, 1997
ACKNOWLEDGMENT
The authors thank Nadia Formina, Anthony Antonopou-
los, MBA, RPh, Winston Turner, RPh, Ron McClintock, and
Rhonda Lyons for technical services and the dialysis nurses
and patients, without whom this study could not have been
done.
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