Nephrol Dial Transplant (1996) 11 (Suppl 3]: 15-21
Nephrology
Dialysis
Transplantation
Comparison of effects of calcitriol and calcium carbonate on secretion of
interleukin-1/? and tumour necrosis factor-a by uraemic peripheral blood
mononuclear cells
Y. Tsukamoto, Y. Nagaba, I. Izumida, T. Morishita and M. Saitoh
Division of Nephrology, Department of Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
Abstract. We studied 26 non-dialysed patients with
chronic renal failure [creatinine clearance (CCr)
32.6+12.7 ml/min]. They were divided into three
groups according to their CCr and serum intact parathyroid hormone (PTH) and were given 0.5 ug/day
oral calcitriol (calcitriol group, « = 8), 3 g/day calcium
carbonate (CaCO3 group, n = 10), or neither (control
uraemic group, w = 8). Serum intact PTH decreased
from 154 + 75 to 90+43 pg/ml in the calcitriol group
(P<0.01) and from 162 ±97 to 77+ 62 pg/ml in the
CaCO3 group (P< 0.001). Calcium carbonate was also
effective in suppressing serum tartrate-resistant acid
phosphatase, alkaline phosphatase and intact osteocalcin levels, while calcitriol did not suppress serum
osteocalcin. Secretion of interleukin-1/J (IL-l/J) and
tumour necrosis factor-a (TNF-a) by phytohaemagglutinin A (PHA)-activated peripheral blood mononuclear cells (PBMC) was greater in uraemic patients
than in age-matched healthy controls (w = 8). Calcitriol
was effective in suppressing secretion of both cytokines,
while calcium carbonate was capable of suppressing
only TNF-a secretion. CCr decreased from 37.4 ±15.4
to 33.0± 11.8 ml/min (i><0.05) in the CaCO3 group,
while it did not decrease in either the calcitriol group
or the control uraemic group during a 6 month period.
These results suggest that supplementation with calcitriol is necessary to maintain bone formation and
normalize IL-l/S and TNF-a secretion by activated
PBMC in uraemic patients.
ment of secondary hyperparathyroidism in nondialysed patients with mild to moderate renal failure.
By the time dialysis therapy is introduced, bone in
most uraemic patients exhibits changes due to secondary hyperparathyroidism [1]. This disorder in bone
usually starts when the glomerular filtration rate
declines below half of the normal value and following
an increase in parathyroid hormone (PTH) secretion
[2]. Thus, it is reasonable to start therapy of secondary
hyperparathyroidism from an early stage of renal
failure. Such therapy could prevent bone resistance to
PTH and hyperplasia of parathyroid glands which are
often seen in end-stage renal failure. However, the
adverse effect of calcitriol on renal function reported
in earner studies on non-dialysed uraemics has discouraged us from treating the non-dialysed patients actively
[3,4]. Later, prospective double-blind studies showed
that these earlier negative findings could be avoided
by reducing the dose to prevent hypercalcaemia and
hypercalciuria {5-7]. At low dosages, oral calcitriol is
proven to be safe and effective in suppressing PTH
secretion in non-dialysed patients as well as in dialysed
patients.
We have another choice for the suppression of PTH
secretion at this stage. In dialysed patients, the independent administration of calcium carbonate was often
useless in suppressing very high PTH secretion. Even
combined therapy with daily oral calcitriol was sometimes not sufficient to suppress PTH secretion once
Key words: calcitriol; calcium carbonate; non-dialysed severe hyperplasia of the parathyroid glands had
uraemics; IL-1/?; TNF-a; peripheral blood mono- developed [8]. However, this is not necessarily true for
non-dialysed patients. We previously reported that 3 g
nuclear cell
oral calcium carbonate given daily was effective in
suppressing PTH secretion without any supplementation with vitamin D3 [9]. Then, the question is
Introduction
raised which regimen should be used primarily for the
treatment of non-dialysed patients. Is there any differThe aim of this study was to clarify the differences of ence in the effect of these two regimens?
effects of calcitriol and calcium carbonate in the treatAnother issue is that serum PTH can reflect the
metabolic changes due to secondary hyperparathyroidCorrespondence and offprint requests to: Y. Tsukamoto, M.D.,
Division of Nephrology, Department of Medicine, Kitasato ism. It is known that target organ resistance to PTH
University School of Medicine, 1-15-1 Kitasato, Sagamihara, is developed in uraemia [10,11]. For this reason, PTH
Kanagawa 228, Japan.
works on target organs at various magnitudes
© 1996 European Dialysis and Transplant Association-European Renal Association
Y. Tsukamoto et al
16
depending on the patient and stage of uraemia. Is there
any non-invasive method to assess metabolic changes
precisely? So far, no serum bone parameters have been
very reliable for predicting bone lesions [12]. In this
study, we employed measurements of interleukin-1/?
(IL-ljS) and tumour necrosis factor-a (TNF-a) secreted
by phytohaemagglutinin A (PHA)-activated peripheral
blood mononuclear cells (PBMC) in order to assess
metabolic changes due to secondary hyperparathyroidism and uraemia. The reasons for this choice are as
follows. First, haematopoietic cells are the only tissues
which can be collected by non-invasive means. Second,
secretion of IL-1/? and TNF-a by monocytes is one of
the key mechanisms in regulation of bone resorption
and formation. Third, these cytokines act on bone
remodelling by different means. Finally, IL-1/? is a
multipotent lymphokine that initiates many metabolic
events including those involving the immune system.
This study was undertaken to determine the differences between calcitriol and calcium carbonate on the
ability to suppress PTH secretion, and to affect renal
function, serum bone parameters, and secretions of
IL-10 and TNF-a by PHA-activated PBMC in nondialysed patients with mild to moderate renal failure.
Subjects and methods
(lOug/ml) for 48 h at a concentration of 106 cells/ml. All
other reagents were purchased from Sigma (St Louis, MO).
Assays
Concentrations of IL-l/J and TNF-a in the supernatant of
cultured media were measured by ELISA using kits
('Interleukin-1/? ELISA Kit', Cistron Biotech., Pine Brook,
NJ and 'Predicta Tumor Necrosis Factor-a Kit', Genzyme
Diagnostics, Cambridge, MA). Serum concentrations of
calcium (corrected by albumin concentrations), phosphorus,
creatinine, and total alkaline phosphatase were determined
with an Auto Analyzer (Hitachi Instruments, Tokyo, Japan).
The serum concentration of intact PTH was measured with
a kit ('Allegro" intact PTH kit', Japan MediPhysics Inc.,
Tokyo, Japan) that recognizes an intact molecule of PTH
[13]. Serum osteocalcin was measured with a kit ('Intact
osteocalcin kit', Teijin Co., Tokyo, Japan) that recognizes an
intact molecule of osteocalcin by an immunoradiometric
assay (IRMA) [14,15]. Serum tartrate-resistant acid phosphatase was measured by an enzyme assay method [16].
Statistics
Results were expressed as the means+ SD. Data collected at
the beginning (pre) and the end of the study (post) were
analysed by paired /-tests using a program for the Macintosh
computer (StatView 4.0, Abacus Concepts Inc., Berkeley,
CA, USA). A level of P<0.05 was considered statistically
significant.
Patients
We studied 26 non-dialysed patients with chronic renal failure
(13 males and 13 females) ranging in age from 30 to 75 years
(mean 52+12 years). Chronic glomerulonephritis was the
cause of the underlying renal failure in all cases. Serum
creatinine ranged from 2.1 to 6.1 mg/dl (mean 3.8 +
1.1 mg/dl) and creatinine clearance (CCr) from 12.1 to
72.7ml/min (mean 32.6+12.7 ml/min). They were divided
into three groups according to their CCr and serum PTH
and were given 0.5 ^g/day oral calcitriol (calcitriol group,
« = 8), 3 g/day calcium carbonate (CaCO3 group, n= 10) or
neither (control uraemic group, « = 8) for 6 months, after a
3 month withdrawal for any vitamin D and phosphate
binder. There were no significant differences in age, serum
creatinine, serum PTH, or CCr among the three groups at
the beginning of the study (determined by ANOVA).
Compliance with the medication regimen and diet instruction
was a criterion for participation in the study. The patients
were instructed to follow a 35 cal/kg body weight diet
containing 0.8 g/kg body weight protein and 600 mg phosphorus. A dietitian interviewed the patients every month
during the study period. Informed consent for participation
was obtained from all patients.
Results
Both calcitriol and calcium carbonate were equally
effective in suppressing PTH secretion in the patients
studied (Figure 1). Serum PTH decreased from
154 ±75 to 90±43pg/ml in the calcitriol group
300
Blood collection and PBMC isolation
Blood samples were obtained 4 h after the ingestion of each
regimen in the morning. PBMC were isolated on a
Lymphoprep" (Nycomed Pharma AS, Oslo, Norway) from
30 ml heparinized blood (lOU/ml). Cells were washed in
PBS, then resuspended and cultured in RPMI medium (Gibco
Lab., Grand Island, NY) supplemented with L-glutamine
300 mg/ml, penicillin 100 U/ml, streptomycin 0.1 mg/ml, 10%
heat-inactivated fetal calf serum (Gibco Lab.) and PHA
pre
Fig. 1. Effect of calcitriol and calcium carbonate on serum intact
PTH levels. Serum PTH levels decreased from 154 ±75 to
90±43pg/ml in the calcitriol group (E2) and from 162 ±97 to
77±62pg/ml in the CaCO3 group (D). No significant change in
serum PTH levels was found in the control ( • ) uraemic group
(159±75 vs 178±108 pg/ml). *i><0.01 vs pre; **P<0.001 vs pre.
Effects of calcitriol and calcium carbonate on IL-l/J and TNF-a secretion
17
Table 1. Effect of each therapy om serum and urinary biochemistry
Control (n = 8)
pre
post
Calcitriol (n = 8)
pre
post
CaCO 3 (n=10)
pre
post
Serum Ca
(mg/dl)
Serum Pi
(mg/dl)
Serum Cr
(mg/dl)
Urinary Ca/Cr
Urinary Pi/Cr
8.4 ±0.6
8.2 + 0.7
3.4+0.9
3.8 + 1.1
3.9 + 1.3
4.5 ±2.0
0.03 + 0.02
0.02 ±0.003
0.45 + 0.03
0.50 ±0.1
8.3 ±0.4
8.7±0.5»*
3.5 + 0.6
3.9+1.1
3.7 + 1.3
4.6±2.6
0.02 + 0.01
0.03 ±0.01
0.45 + 0.07
0.45 ±0.2
8.3 + 8.6
8.6±0.5*»
3.6 + 0.7
3.4 + 0.7
3.9+1.0
4.8 + 1.8*
0.02 + 0.003
0.02 ±0.007
0.42 + 0.09
0.37 ±0.11
'
pre, at the beginning of each therapy; post, at the end of each therapy.
*P<0.01 vs pre; **P< 0.005 vs pre.
(P<0.01) and from 162 + 97 to 77±62pg/ml in the
CaCO3 group (P<0.001). During the same 6 month
period, no significant change in serum PTH was found
in the control group (159 + 75 vs 178 + 108pg/ml).
Serum calcium increased significantly with both calcitriol and CaCO3 administration (Table 1). However,
there was no significant change in serum phosphorus
in either group (Table 1). Neither CCr nor serum
creatinine changed significantly during the 6 month
period in either control or calcitriol groups (Figure 2
and Table 1). However, CCr decreased from
37.4±15.4 to 33.0 +11.8 ml/min (P<0.05) and serum
creatinine increased from 3.9 + 1.0 to 4.8+ 1.7 mg/dl
(P<0.01) in the CaCO3 group. There were no significant changes in urinary calcium/creatinine ratio or
urinary phosphorus/creatinine ratio before and after
therapies in any of the groups (Table 1).
The effects on serum bone parameters for osteoblastic activities were different in the patients receiving
calcitriol and those receiving calcium carbonate admin-
istration (Table 2). Serum alkaline phosphatase
decreased significantly from 218 + 76 to 161+46IU/1
in the CaCO3 group (P<0.02). This decrement was
less in the calcitriol group (from 220 + 79 to
195±69IU/1, i ) <0.05). This difference between the
two groups was more pronounced for the changes of
serum osteocalcin. Serum osteocalcin decreased from
20.8 + 12.0 to 13.1+ 10.7 ng/ml in the CaCO3 group
(P<0.001). However, no significant change was found
in the calcitriol group (13.8 + 8.0 vs 16.2±8.7 ng/ml).
Serum tartrate-resistant acid phosphatase, the parameter for osteoclastic activities, was significantly suppressed by both calcitriol and calcium carbonate
administration. The effect was also more significant in
the CaCO3 group (P< 0.001) than in the calcitriol
group (P<0.05).
Both IL-l/S and TNF-a concentrations in the cultured media of PHA-activated PBMC were greater in
patients than in age-matched healthy controls (Figures
3 and 4). TNF-a concentrations decreased significantly
both in the CaCO3 group (P<0.05) and the calcitriol
group (P<0.01). IL-l/J concentrations decreased
significantly from 3.18 + 1.69 to 1.37+0.94 ng/ml
(i><0.005). There were no significant changes in IL-1/?
Table 2. Effect of each therapy on serum parameters for bone
metabolism
pre
Fig. 2. Effect of calcitriol and calcium carbonate on creatinine
clearance (CCr). CCr did not change significantly in the control
uraemic group ( • , 27.2±5.9 vs 26.3±7.7 ml/min) or the calcitriol
group (0, 32.1 ± 13.2 vs 31.0± 11.0 ml/min). CCr decreased significantly from 37.4± 15.4 to 33.0± 11.8 ml/min in the CaCO3 group (D).
*P<0.05 vs pre.
Control (n = 8)
pre
post
Calcitriol (n = 8)
pre
post
CaCO 3 (n=10)
pre
post
Normal range
BGP
(ng/ml)
Al-p
(IU/1)
TRACP
(U/l)
224 + 50
241 + 43
20.7 ±3.6
17.5±8.1
14.6 ±4.7
14.4 ±5.3
220 + 79
195 ±69*
20.7+4.4
14.1 ±3.7*
13.8±8.0
16.2±8.7
218 + 76
161+46*
73-248
20.8+4.8
11.6 + 2.9**
5.5-17.2
20.8 ±12.0
13.7 + 10.7**
<6.8
Al-p, serum total alkaline phosphatase level; TRACP, tartrateresistant acid phosphatase level; BGP, serum intact osteocalcin level.
*P<0.05 vs pre; **.P<0.001.
Y. Tsukamoto et aL
18
post
pre
healthy
Fig. 3. Effect of calcitriol and calcium carbonate on IL-l/J secretion
by PHA-activated PBMC. IL-l/J levels in incubated media were
higher in the three patient groups than in healthy controls
(1.9±1.1 ng/ml, n = 8). They decreased significantly from 3.2+1.7
to 1.4 ±0.9 ng/ml in the calcitriol group (63, n = 8). No significant
changes were observed in either the control uraemic ( • , 2.4± 1.1 vs
2.0±2.6ng/ml, n = 8) or the CaCO3 group (D, 2.9±2.2 vs
2.0± 1.4 ng/ml, n = 10). */><0.05 vs pre.
7-,
6-
I
5-
I]
2 32-
*
1
II
I
1
1-
i
Jr• i
0-
pre
post
healthy
Fig. 4. Effect of calcitriol and calcium carbonate on TNF-oc secretion
by PHA-activated PBMC. TNF-a levels in incubated media were
higher in the three patient groups than in healthy controls
(2.5± 1.0 ng/ml, n = 8). They decreased significantly from 4.3 + 2.0
to 2.1 + 1.4 ng/ml in the calcitriol group (0, n = 8) and from 4.2 + 3.4
to 1.4±1.1 ng/ml in the CaCO3 group (D, n = 10). No significant
changes were observed in the control uraemic group ( • , 3.6 + 2.3
vs 2.4±1.1 ng/ml, n = 8). *P<0.05 vs pre.
concentrations in the CaCO3 and the control uraemic
group.
Discussion
This study confirmed the result of our previous study
which first demonstrated the effectiveness of calcium
carbonate in suppressing PTH secretion without a
supplement of any vitamin D metabolite in patients
with mild to moderate renal failure (CCr
12-72 ml/min) [9]. This study also confirmed the previous studies which demonstrated the effectiveness of
oral calcitriol in suppressing PTH secretion in nondialysed patients [5-7]. Calcium carbonate, which is
an alternative phosphate binder of aluminium compounds, has been used for the last decade in dialysed
patients. This phosphate binder is usually administered
together with calcitriol in patients with advanced renal
failure, because calcium carbonate alone is not usually
powerful enough to suppress increased PTH secretion.
However, this combined therapy often causes hypercalcaemia unless a lower Ca2+-containing dialysate (Ca2+
2.5mEq/l) is used. These experiences in dialysed
patients mean that we should be very careful in choosing the method of suppressing PTH secretion in nondialysed patients, because hypercalcaemia usually
results in further damage to renal function.
Thus, we should pay special attention to the adverse
effects of therapeutic regimens on renal function as
well as to effectiveness. Earlier studies showed that
giving calcitriol to non-dialysed patients resulted in the
further deterioration of their renal function [3,4]. These
negative results therefore prevented most physicians
from using calcitriol in non-dialysed patients. However,
lower doses of calcitriol that could prevent hypercalcaemia and hypercalciuria have recently been proven not
to deteriorate renal function [5-7]. The present study
also rejected the negative result of earlier studies,
because 0.5 ug/day calcitriol did not cause a .significant
decrease in creatinine clearance. On the contrary,
3 g/day calcium carbonate caused a significant decrease
in both creatinine clearance and serum creatinine
during the 6 month study period. Since there were no
significant changes in creatinine clearance in either the
calcitriol group or in the control uraemic group during
the same period, the decrement of creatinine clearance
in the CaCO3 group should be considered as specific
for calcium carbonate administration. Our previous
study has already shown the same result [9]. The
reason for this discrepancy is not clear. Both calcitriol
and calcium carbonate increased serum calcium significantly. The magnitude of these increments was identical for both regimens. Neither changed urinary
calcium excretion or serum phosphorus; however,
changes in creatinine clearance do not always mean
changes in the GFR. Bertoli et al. compared creatinine
clearance with inulin clearance during treatment with
calcitriol [17]: creatinine clearance decreased while
inulin clearance did not. They suggested that calcitriol
increased the absorption or decreased the secretion of
creatinine by the nephron. Thus, a precise method for
measuring GFR, such as inulin clearance or iodothalamate clearance, should be employed to define the effect
of these regimens on renal function.
The present study showed that 3 g/day calcium
carbonate was more potent in suppressing serum PTH
than 0.5 ug/day calcitriol. The improvement of metabolic acidosis by this alkali should favour a suppressed
PTH as well [18-20]. Further, suppression of serum
PTH by calcium carbonate caused more suppression
Effects of calcitriol and calcium carbonate on IL-1/? and TNF-a secretion
of serum tartrate-resistant acid phosphatase and serum
alkaline phosphatase levels. Since tartrate-resistant
acid phosphatase is a specific enzyme of osteoclasts,
increased serum values are observed in hyperparathyroid bone. However, specificity of serum concentration
as a diagnostic index is not very high [12]. Our study
showed a positive correlation of serum tartrateresistant acid phosphatase with osteoclastic surface
(r=0.38, w=40). Although serum alkaline phosphatase
is composed of isoenzymes produced in the intestine,
liver, kidney and bone, measurement of serum values
can provide an indication of increased osteoblastic
activity in bone [21]. Significant increases in these two
parameters in our patients indicate that most of the
patients suffered hyperparathyroid bone and either
calcium carbonate or calcitriol was effective in suppressing these serum parameters. However, the effect
on another bone parameter, serum intact osteocalcin,
was different between the two therapies. Calcitriol
supplement sustained serum intact osteocalcin, while
calcium carbonate suppressed it. This discrepancy of
the effect on osteoblastic activity was not surprising,
because calcitriol stimulates the production of osteocalcin [15]. Osteocalcin is a bone Gla protein secreted by
osteoblasts [22,23]. The exact role of this protein has
not been established, but a positive correlation has
been demonstrated between its serum concentrations
and osteoblastic activity [24,25]. Our unpublished data
indicate that the intact osteocalcin assay is more
specific than the conventional C-terminal assay because
proteolysed fragments of osteocalcin are accumulated
by renal failure. Intact osteocalcin correlated positively
with the bone formation rate better than with the
C-terminal assay in 26 dialysed patients (r = 0.669 vs
0.538). These results suggest that calcitriol has an
advantage over calcium carbonate in maintaining bone
formation.
Only a few papers reported the cytokine secretions
by PBMC in uraemic patients, and they reached different conclusions. Herbelin et al. demonstrated the
increased basal production of IL-1/? and TNF-a by
uraemic PBMC in non-dialysed patients with end-stage
renal failure [26]. They also found increased serum
IL-10 but TNF-a [27]. Powell et al. did not find
increases of either serum IL-1/? or TNF-a. Increased
serum TNF-a was found only by endotoxin stimulation
in both non-dialysed and dialysed patients [28]. In
haemodialysed patients, Haran et al. did not find any
difference in TNF-a production by either spontaneous
or activated PBMC compared with healthy controls;
and 8 week administration of la(OH)D3 increased
TNF-a production by activated PBMC [29]. In contrast, Riancho et al. found that calcitriol induced a
progressive reduction of TNF secretion by activated
PBMC [30]. They also found that calcitriol therapy
resulted in significant increases in the phorbol myristate
acetate-induced secretion of IL-1 and IL-6 by PBMC
of haemodialysed patients. However, this was a transient effect, observable by day 7 of therapy but no longer
evident by day 30. These discrepancies among studies
19
might be due to differences in dialysis conditions,
history of dialysis, and other environmental factors.
The increased secretion of cytokines by activated
PBMC in non-dialysed uraemic patients might cause
some clinical manifestations of uraemia. In the bone
microenvironment, several types of cells interact with
each other for bone remodelling. Among the cells,
monocytes secrete IL-1/? and TNF-a, which stimulate
bone resorption [31,32]. Since TNF-a acts on osteoblasts and down-regulates PTH receptors in osteoblastlike cells in vitro [33,34], the increased production of
TNF-a in uraemia might be one of the mechanisms
for producing bone resistance to PTH. TNF-a also
inhibits l,25(OH)2D3-stimulated osteocalcin synthesis
by osteoblast-like cells m vitro [35,36]. This suggests
that increased TNF-a production by uraemic PBMC
could cause a mineralization disorder in renal
osteodystrophy.
IL-1 is a multipotent lymphokine that works not
only on bone cells but also on the immune system,
epidermal cells, vascular endothelial cells, smooth
muscle cells, fibroblasts, pituitary cells, and mesangial
cells. IL-1 stimulates the production of other cytokines
to initiate many reactions, including inflammation.
Thus the overproduction of these cytokines in uraemia
must result in various clinical manifestations.
Monitoring of the production of these cytokines by
PBMC is a useful non-invasive method to determine
uraemic disorders. The present study demonstrated
that calcitriol supplement was very effective in normalizing cytokine over-secretion; calcium carbonate was
less effective in suppressing IL-1/? production. These
results suggest that supplement of calcitriol is necessary
not only for suppressing increased PTH secretion for
bone but also for preventing some uraemic extra-bone
manifestations including immune disorders.
Finally, we have to be careful to avoid excessive
suppression of PTH secretion by these treatments. The
potential risk associated with these therapies is the
development of adynamic bone disease due to excess
suppression of PTH, which is a well-known problem
in dialysis patients [37]. Hernandez et al. recently
reported that 30 of 92 non-dialysed patients with endstage renal failure also exhibited an adynamic bone
without stainable bone aluminium [38]. This study
demonstrated that patients with adynamic bone disease
were older and had a lower serum intact PTH compared with the non-adynamic bone patients (179 + 31
vs 432 + 62 pg/ml). It is obvious from this study that
these patients require much greater PTH concentrations than healthy persons to maintain a normal bone
turnover. However, the patients with more normal
GFR require much less PTH. Bianchi et al. suppressed
mean serum intact PTH from 109 to 81.6 pg/ml by the
combined administration of calcitriol and calcium carbonate in non-dialysed patients with creatinine clearances between 64 and 36ml/min [39]. Histology
revealed no occurrence of adynamic bone disease in
these patients at the end of therapy. Thus, bone
resistance to PTH is minimum in patients with mild
renal failure. Since some of the patients in our study
20
showed lower creatinine clearance values, greater PTH
would be required to maintain a normal bone turnover.
In conclusion, both calcitriol and calcium carbonate
were effective in suppressing PTH secretion without
causing hypercalcaemia and hypercalciuria in patients
with mild to moderate renal function. When given at
0.5 ug/day, calcitriol did not decrease CCr during a 6
month period. There is a possibility that calcium
carbonate might be harmful to renal function. These
results suggest that calcitriol supplement is necessary
to maintain bone formation and normalize IL-1/? and
TNF-a secretion by activated PBMC in patients with
uraemia.
Acknowledgements. This work was supported by the Program Project
Grant from the Ministry of Health and Welfare of Japan. Part of
this study was also presented at the 27th Annual Meeting of the
American Society of Nephrology, Oct. 26-29, 1994, Orlando, FL,
USA.
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