Nephrol Dial Transplant ( 1997) 12: 514518

Nephrology
Dialysis
Transplantation

Original Article

High-dose alfacalcidol improves anaemia in patients on haemodialysis

S. Albitar, R. Genin, M. Fen-Chong, M.-O. Serveaux, D. Schohn and C. Chuet
Department of Nephrology, Felix Guyons Hospital, St Denis, France

Abstract
Background. Alfacalcidol is efficient for treating secondary hyperparathyroidism in patients on maintenance haemodialysis ( HD). Little is known about the
direct impact of high-dose alfacalcidol on anaemia in
end-stage renal failure. We therefore carried out a
prospective study over 18 months to examine the direct
effect of high-dose alfacalcidol on erythropoiesis in
erythropoietin (rHuEpo)-dependent anaemic patients
on HD for more than 6 months with moderate hyperparathyroidism.
Study design. Twelve patients received oral alfacalcidol
at a dosage of 67 mg per week and calcium carbonate
during the first 12 months, calcium carbonate without
alfacalcidol during the next 3 months, and again
alfacalcidol and calcium carbonate during the last 3
months. Criteria for selection were haemoglobin <10
g/dl, iPTH >250 pg/ml, transferrin saturation
( TS) >25%, S-ferritin >300 mg/l, and S-aluminium
<40 mg/l.
Results. Haemoglobin (Hb) and reticulocyte counts
increased during the first phase, decreased and returned
to a baseline prior to starting vitamin D treatment in
the second phase, and again increased when alfaclcidol
was reintroduced, whereas iPTH decreased during the
first 3 months of the first phase and then remained
stable, as did S-calcium, which increased during
the first 3 months and then remained constant.
S-phosphate increased during the first and third phases,
and decreased during the second phase. Two patients
during the first phase and one patient during the third
phase presented hypercalcaemia; requiring a temporary
discontinuation of alfacalcidol.
Conclusion. High-dose alfacalcidol is efficient in
anaemic patients with moderate hyperparathyroidism
on maintenance HD and has a direct effect on erythropoietic cells regardless of serum calcium and iPTH
levels.
Key words: high-dose alfacalcidol; anaemia; haemodialysis; moderate hyperparathyroidism

Introduction
Anaemia is one of the more constant clinical features
in patients on maintenance haemodialysis (HD). The
aetiology of anaemia in these patients is multifactorial.
The major factors seem to be inappropriate low serum
erythropoietin, functional iron deficiency, dialysis
insufficiency, aluminium overload, and secondary
hyperparathyroidism ( HPT ) [19].
High-dose calcitriol, the active form of vitamin D,
is widely used in haematological disorders [ l011 ] and
HPT treatment [1214 ]. Furthermore, in vitro and
other studies indicate that bone marrow erythropoietic
cells have specific receptors for calcitriol, and calcitriol induces proliferation and maturation of stem
cells[46,10,11]. The present study was designed for
evaluation of direct effect of high-dose alfacalcidol on
anaemia without recombinant human erythropoietin
(rHuEpo) throughout the study in anaemic patients
on HD with moderate HPT, who were, 1 month before,
under rHuEpo, for 18 months of follow-up.

Subjects and methods

Patients
Twelve patients, from a total population of 200 patients in
six haemodialysis units, on maintenance HD for at least 6
months and without rHuEpo therapy or calcitriol for at least
1 month before the study, iPTH >250 pg/ml (normal 55)
and haemoglobin concentration ( Hb) <10 g/dl were selected.
They were eight males and four females, with a mean age
5914 years. The mean duration of HD was 134 179
months. There were seven patients with the diagnosis of
chronic glomerulonephritis, two had chronic tubulointerstitial nephritis, and three were of unknown aetiology. We
excluded all patients with iron, folate or vitamin B defi12
ciency, serum aluminium exceeding 40 mg/l, active bleeding
lesions, active untreated infection, malignancies or other
causes of inflammation, and also patients with medications
that affect erythropoiesis or bone homeostasis such as angiotensin-converting enzyme inhibitors, aluminium compounds,
or corticosteroid therapy.

Dialysis programme
Correspondence and offprint requests to: Dr Sami Albitar, Department
of Nephrology, Felix Guyons Hospital, 97400 St Denis, France

All patients underwent dialysis three times a week, utilizing

bicarbonate-buffered dialysate with calcium ( 1.5 mmol/l ) and

1997 European Renal AssociationEuropean Dialysis and Transplant Association

Alfacalcidol and anaemia in haemodialysis patients

515

polysulphone dialysers, and were being managed to maintain

their Kt/V (urea) >1 and protein catabolic rate (PCR) 11.2
g/kg/day ( Table 1). The average length of HD sessions was
40.29 h (range 45 h).

Study design
The study, which was for 18 months, was subdivided into
three phases:
The first phase was the first 12 months during which all
patients were treated with alfacalcidol and calcium carbonate.
The second phase was the next 3 months, during which all
patients were treated with calcium carbonate without alfacalcidol for maintaining constant serum calcium and iPTH
levels. The third phase was the last 3 months, during which
all patients were treated with alfacalcidol and calcium
carbonate.
The dose of alfacalcidol was decreased or increased weekly
to maintain serum calcium above 2.2 mmol/l and below
3 mmol/l and serum phosphorus below 2.5 mmol/l; as was
calcium carbonate which was given as phosphate chelator
exclusively.

Measurements
Haemoglobin, absolute reticulocyte counts, serum calcium
and serum phosphorus were monitored weekly. Serum iron,
TS were assessed monthly. iPTH, serum ferritin (at least
1 week after the last iron infusion) by radioimmunoassay,
cyanocobalamine, intra- and extraerythrocytic folate, serum
albumin by nephelometry and serum aluminium were
measured quarterly. Kt/V was calculated according to
Daugirdas [15] and PCR was calculated according to Gotch
and Sargent [ 16 ] monthly.

Statistical analysis
All data are presented as means standard deviation of the
mean of the total measurement per period. Statistical differences between periods were calculated by two-tailed Student
test, the patients acting as their own controls.

Results
None of the patients selected used other medication
known to affect erythropoiesis or bone mineral metabolism during the study, and all patients completed
the study without any intercurrent problem. No
patients dropped out.
Haemoglobin concentration (Figure 1)
Haemoglobin was 8.71.2 g/dl before treatment,
10.30.8 g/dl at 3 months (P<0.005 vs before),

10.80.9 g/dl at 6 months, and 10 70 9 g/dl at 12

months (n.s. vs 3 months), 8.90.6 g/dl at 15 months
(P<0.005 vs 12 months), and 10.50.6 g/dl at 18
months (P<0.005 vs 15 months).There was an increase
in Hb during the first 3 months P<0.005 vs before),
a stabilization in Hb during the next 9 months (n.s.),
a decrease in Hb during the second phase (P<0.005
vs 12 months), and a re-increase in Hb during the
third phase (P<0.005 vs 15 months).
Absolute reticulocyte counts (Figure 2)
Reticulocyte counts increased during the first phase
and reached a maximum at 12 months (P<0.005 vs
before), decreased abruptly during the second phase
(P<0.005 vs 12 months), and re-increased during the
third phase (P<0.005 vs 15 months).
Serum iPTH, calcium and phosphorus levels (Figure 1)
There were a decrease in iPTH levels and an increment
in S-calcium during the first 3 months (P<0.005 vs
before) and a progressive stabilization in iPTH and
S-calcium levels during the next 15 months (n.s.).
Two patients during the first phase and one during
the third phase presented hypercalcaemia, necessitating
a temporary discontinuation of alfacalcidol and calcium carbonate for 2 weeks. The mean serum phosphorus levels, which were statistically higher under
alfacalcidol (P<0.005), were within the low normal
range in the second phase because of alfacalcidol
discontinuation, increase in calcium carbonate dosage,
sustained S-PTH secretion, and normal phosphorus
intake.
Iron status, S-aluminium and S-albumin levels
Iron status, which was assessed by TS and serum
ferritin, was constant throughout the study (Figure 2 ).
S-ferritin, which was higher during the second and
third phases, but remained statistically insignificant
(n.s. vs before). TS was >25% throughout the study.
S-aluminium levels were <40 mg/l during the study
period ( Table 1). Aluminium compounds were avoided
in all patients selected, since a form of low turnover
osteodystrophy and anaemia was noted with oral
aluminium exposure [9,12,13].
Nutritional state, which was assessed by S-albumin,
was good throughout the study; as were dialysis
parameters (Table 1 ).

Table 1. Mean (SD) S-albumin, S-aluminium, and dialysis parameters

S-albumin (g/l )
S-aluminium ( mg/l )
Kt/V
Protein catabolism rate (g/kg/day)

Baseline

3 months

6 months

12 months

15 months

18 months

38.171.47
20.88.2
1.190.07
1.130.08

38.421.31
13.23.2
1.220.08
1.140.08

38.161.46
14.32.3
1.210.10
1.170.08

39.411.30
14.31.2
1.20.06
1.130.08

38.251.10
15.32.1
1.20.08
1.110.07

39.751.14
15.75.5
1.190.08
1.130.06

516

Fig. 1. Mean concentration of haemoglobin, iPTH, S-calcium, S-phosphate and mean weekly dosage of alfacalcidol

Fig. 2. Mean absolute reticulocyte counts, transferrin saturation and S-ferritin

S. Albitar et al.

Alfacalcidol and anaemia in haemodialysis patients

Alfacalcidol and calcium carbonate doses

The dose of alfacalcidol was temporarily reduced in a
few cases from 7 to 3 or 4 mg weekly because of high
serum calcium or high phosphorus levels. In absolute
values, the mean alfacalcidol dose was 6.11.5 mg per
week during the first phase and 5.81.2 mg per week
during the third phase; the mean calcium carbonate
dose was 8.22 3 g daily during the first phase,
10.12.4 g daily during the second phase, and
7.13.5 g daily during the last phase.
Iron intravenous substitution and need for transfusions
Intravenous iron, which was exclusively used, was
indicated when TS was <25% and/or S-ferritin
<500 mg/l.
The mean individual intravenous ferric hydroxide
polymaltose
dose
was
40060 mg/month,
33349 mg/month before and during the study
respectively. No patients were transfused throughout
the study.

Discussion
The present study clearly shows the positive impact of
high-dose alfacalcidol on anaemia and moderate secondary hyperparathyroidism in HD patients with a
good iron status and efficacious dialysis parameters.
Previous studies in myeloplastic anaemia [10,11] and
in anaemia with end-stage renal failure on HD or
peritoneal dialysis [46 ] found improvement of
anaemia with high-dose alfacalcidol.
iPTH, which has a direct inhibitory effect on erythropoiesis, increases bone marrow fibrosis, decreases
erythrocyte survival, interferes with Epo production
and is a resistance factor in rHuEpo therapy, is one of
the mechanisms suggested [48], but in our study
iPTH decreased during the first 3 months of the first
phase and then remained stable throughout the study,
while Hb increased during the first phase, decreased
and returned to a baseline prior to starting vitamin D
treatment in the second phase, and increased again
when alfaclcidol was re-introduced ( Figure 1 ). We
cannot thus consider iPTH suppression as the only
factor resulting in an improvement of anaemia.
In vitro studies indicate that the culture medium
calcium concentration improves the response of bone
marrow erythropoietic cells to rHuEpo [6 ], but in our
study S-calcium was increased during the study period,
whereas Hb dropped during the second phase; suggesting that S-calcium is not the main factor explaining
the improvement of anaemia.
In fact there are few reports [46,10,11] concerning
the direct effect of calcitriol on erythropoiesis with or
without renal failure, but our study clearly documents
that alfacalcidol in a high dose has a positive effect,
independently of S-PTH and S-calcium, on anaemia
in HD populations; however, the mechanism of its
action remains to be elucidated.

517

Functional iron deficiency and aluminium overload

were carefully avoided in this trial by displacing TS
towards more than 25%, S-ferritin >500 mg/l, parenteral administration of iron salt during HD sessions,
and calcium carbonate as exclusive phosphate
chelator [3].
In agreement with other studies[14], the selection of
high-dose oral alfacalcidol engenders much inconvenience: (i) an important rise in S-calcium (2 patients in
the first phase and 1 patient in the last phase), (ii) a
substantial increase in S-phosphate, explaining the
negative effect of alfacalcidol on long-term iPTH levels,
which were not reduced to the normal range except in
four patients within the high normal range and one
patient within the low normal range, (iii) an induction
of adynamic bone disease, an important subject of
debate, in patients within the low range iPTH concentrations without aluminium intake [12,13], and (iv) an
increase in the CaP ion products, a propensity
toward soft-tissue calcification.
In the second phase a higher S-calcium compared
to normal (as evidenced by a higher set point ) and a
lower S-phosphate were required to sustain iPTH
secretion.
We acknowledge that the number of subjects selected
was small in this study and lacked a control group,
but our selection criteria and study design were rigorous in order to use all patients as their own controls
,and to obtain a rational conclusion from our results.
We conclude that high-dose alfacalcidol is efficient in
anaemic patients with moderate HPT on maintenance
HD, and has a direct effect on erythropoiesis, but its
adverse effects of vitamin D must be taken into consideration. Further studies are necessary to confirm
these results.

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Received for publication: 6.5.96
Accepted in revised form: 1.11.96