109-Adachi final 41.pdf - Advances in Peritoneal Dialysis

Advances in Peritoneal Dialysis, Vol. 22, 2006
Yoko Adachi, Yusuke Nakagawa, Akira Nishio
In Patients Treated with
Peritoneal Dialysis,
Icodextrin Improves
Erythropoietin-Resistant
Anemia Through Blockade
of Asialo Receptors on
Hepatocytes
Although erythropoietin (EPO) derivatives improve
anemic status in most end-stage renal disease patients,
some EPO-resistant patients remain. Asialo-type EPO
is as effective as is native EPO in vitro, but in vivo, it
is quickly trapped by the hepatic asialo receptors.
Alkaline phosphatase (ALP) also binds to the asialo
receptor for degradation.
We compared hematologic indices in 27 stable PD
patients 1 – 3 months before and after the start of
icodextrin solution. In selected patients, we also performed
imaging with 99m-technetium–labeled galactosyl
serum albumin (GSA) for asialo receptors.
Resistance to EPO was defined as a hematocrit below
30% concurrent with EPO administration of more
than 18,000 IU monthly.
In 19 patients without EPO resistance started on
icodextrin, the average hematocrit level did not
change (–1.2%), and the average ALP activity increased
36%. But in 8 patients with EPO resistance,
the average hematocrit level increased by 12% (p =
0.03 as compared with baseline), and ALP activity
increased by 79% (p = 0.02 as compared to non EPO
resistant cases) after icodextrin introduction. In the
patients with marked elevation of ALP activity, GSA
scintigraphy showed inhibition of tracer binding.
These results indicate that improvement in EPOresistant
anemia and greater ALP activity with
icodextrin administration are mediated through
blockade of the asialo receptors on hepatocytes.
From: Department of Medicine, Kobe Central Hospital of
Social Insurance, Kobe, Japan.
Key words
Icodextrin, erythropoietin, asialo receptor, alkaline
phosphatase
Introduction
Anemia is one of the key issues in the management
of end-stage renal disease patients. The introduction
of erythropoietin (EPO) derivatives dramatically improved
not only anemia per se, but also prognosis
and quality of life in these patients (1,2). However,
a substantial number of EPO-resistant patients remain,
and various causes of EPO resistance have
been reported (3,4). Mammalian native EPO is metabolized
into the asialo type by serum sialidase, and
asialo-type EPO is more effective than is native EPO
(sialo-type) in vitro; however, the asialo-type is much
less effective in vivo because of its rapid disappearance
from serum by binding to the asialo receptors on
hepatocytes (5,6).
Icodextrin is an osmotic amylopectin molecule
used in peritoneal dialysis (PD) solution; it known to
be degraded into oligomaltoses by amylase activity
in serum. The serum concentration of the end product,
maltose, reaches the steady state at approximately
1 g/L when one bag of icodextrin solution is used daily
(7). On the other hand, Blom et al. (8) reported that
the alkaline phosphatase (ALP) protein can bind to
asialo receptors and can then be internalized into
lysosomes in hepatocytes for degradation. Gokal
et al. speculated that the increase in ALP activity
in patients using icodextrin is attributable to delay of
the ALP protein’s degradation, because icodextrin metabolites
block receptor binding (9). We hypothesized

42 Adachi et al.
that this blockade could be indirectly proved by imaging
with 99m-technetium–labeled human galactosyl
albumin ( 99m Tc GSA).
Considering this background, we found that EPOresistant
anemia improved in patients using icodextrin
solution. Moreover, those patients simultaneously
showed a greater increase in ALP activity than did
patients without EPO resistance. The mechanism of
the improved anemia in EPO-resistant patients therefore
seems to reflect blockade of asialo receptors and
delayed breakdown of the ALP protein.
Patients and methods
We analyzed 27 stable patients on PD with icodextrin
solution. We compared hematologic indices before and
1 – 3 months after the initiation of icodextrin solution.
We performed liver imaging with 99m Tc GSA for
asialo receptors in 3 patients before and after the use
of icodextrin. We defined EPO resistance as a hematocrit
below 30% with concurrent administration of
more than 18,000 IU EPO monthly. Statistical analyses
used the paired or unpaired t-test, and we accepted
p values of 0.05 or less as statistically significant.
Results
Table I shows the changes of hematocrit and ALP activity
in patients with and without EPO-resistant anemia
after icodextrin use. In 19 patients without
EPO-resistant anemia, the average hematocrit level
did not change significantly (–1.2%), and ALP activity
increased only 36% from the baseline level. On
the other hand, in 8 patients with EPO resistance, the
average hematocrit increased 12% (p = 0.03 as compared
with baseline, by paired t-test), and ALP activity
rose by 79% (p = 0.02 as compared with that
in patients without EPO resistance, by unpaired t-
test). In the graphs for all 27 individual patients
(Figure 1), we found no linear correlation between
the percentage increase in hematocrit and ALP activity
from baseline.
Figure 2 shows a representative liver imaging
study by 99m Tc GSA scintigraphy in a patient with
marked elevation of ALP activity. The LHL 15 reading,
which indicates tracer binding to hepatocytes,
showed a normal value before the use of icodextrin;
after icodextrin use, it showed moderately impaired
uptake. In patients with a slight elevation of ALP activity,
GSA scintigraphy showed no apparent change
from the initial imaging performed before icodextrin
use (Data not shown).
Discussion
In the present study, we show for the first time that
icodextrin improves EPO-resistant anemia in PD patients.
The possible mechanism seemed to be at least
partly related to an elevation of serum ALP activity,
because the increase of ALP activity in patients with
EPO-resistant anemia was significantly higher than
that in patients with a hematocrit of 30% or more,
although a linear correlation between the improvement
in hematocrit and the elevation of ALP activity
was not achieved.
Since the early stages of erythropoietin development,
glyco-moiety in the molecule has been regarded
as essential for its in vivo activity, because a rapid
disappearance of erythropoietin from serum was observed
when the sialic acid at the end of intact molecule
was removed by sialidase in serum (5,6). On
TABLE I Mean hematocrit and alkaline phosphatase (ALP)
activity before and after icodextrin use
Hematocrit (%) ALP (U/L)
EPO- Not EPO- Not
resistant resistant resistant resistant
Before 25.7±3.2 34.1±3.7 234±34 236±79
After 28.7±4.5 33.7±4.5 419±109 322±147
Change (%) 12 –1.5 79 36
p Value 0.03 NS 0.002 0.002
EPO = erythropoietin; NS = nonsignificant.
FIGURE 1 Changes of alkaline phosphatase (ALP) and hematocrit
(Hct) before and after icodextrin introduction (all patients).

Icodextrin Improves EPO-Resistance 43
of asialo-form erythropoietin, with a consequent slight
improvement in anemia. It might be argued that the
observed elevation in hematocrit is attributable to
plasma condensation in these patients because of increased
ultrafiltration with icodextrin; however, this
explanation is unlikely because other biochemical indices
did not change (Data not shown).
Further studies are warranted to prove whether the
serum level of erythropoietin increases with the use
of icodextrin in resistant patients. We also need to
clarify why patients with a hematocrit of 30% or more
did not show a further increase in that value even
though their ALP level was somewhat higher. And a
last question to be investigated in the future is why
some patients showed a marked increase in ALP activity,
but some did not, even though all used
icodextrin solution in the same way.
Conclusions
Icodextrin improved EPO-resistant anemia, and the
mechanism seems to relate to blockade of the hepatic
asialo receptors by icodextrin metabolites.
FIGURE 2 Receptor imaging with 99m Tc galactosyl serum albumin
scintigraphy before (upper panel) and after (lower panel)
icodextrin use.
the other hand, as Blom et al. reported (8), ALP protein
contains a galactose moiety at the end of its molecule,
and blockade of the asialo receptor significantly increased
ALP serum activity because of delayed degradation
of the protein. Gokal et al. speculated that the
increase of ALP activity in patients using icodextrin
solution might involve the same mechanism as that for
icodextrin metabolites (9). In proving this hypothesis
(as shown by 99m Tc GSA scintigraphy imaging of asialo
receptors), we also demonstrated that only icodextrin
users with increased ALP activity showed the inhibited
receptor binding. The images suggest that the increased
ALP activity is attributable to blockade of the
hepatic asialo receptors by icodextrin metabolites, with
a consequent delay in ALP breakdown.
Taking these findings together, we speculate that
blockade of the asialo receptors by icodextrin
metabolites also caused blockade of the degradation
References
1 Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray
DC, Barré PE. The impact of anemia on cardiomyopathy,
morbidity, and mortality in end-stage renal
disease. Am J Kidney Dis 1996; 28:53–61.
2 Pollock CA. The impact of guidelines for the prevention
of anemia on clinical outcome. Perit Dial Int
2005; 25(Suppl 3):S99–101.
3 Macdougall IC. Poor response to erythropoietin:
practical guidelines on investigation and management.
Nephrol Dial Transplant 1995; 10:607–14.
4 Macdougall IC. Hyporesponsiveness to anemia
therapy—what are we doing wrong? Perit Dial Int
2001; 21(Suppl 3):S225–30.
5 Takeuchi M, Takasaki S, Shimada M, Kobata A. Role
of sugar chains in the in vitro biological activity of
human erythropoietin produced in recombinant Chinese
hamster ovary cells. J Biol Chem 1990;
265:12127–30.
6 Briggs DW, Fisher JW, George WJ. Hepatic clearance
of intact and desialylated erythropoietin. Am J
Physiol 1974; 227:1385–8.
7 Plum J, Gentile S, Verger C, et al. Efficacy and safety
of a 7.5% icodextrin peritoneal dialysis solution in
patients treated with automated peritoneal dialysis.
Am J Kidney Dis 2002; 39:862–71.
8 Blom E, Ali MM, Mortensen B, Huseby NE.
Elimination of alkaline phosphatase from circulation

44 Adachi et al.
by the galactose receptor. Different isoforms are
cleaved at various rates. Clin Chim Acta 1998;
270:125–37.
9 Gokal R, Moberly J, Lindholm B, Mujais S. Metabolic
and laboratory effect of icodextrin. Kidney Int
2002; 62(Suppl 81):S62–71.
Corresponding author:
Yoko Adachi, MD, Department of Medicine, Kobe
Central Hospital of Social Insurance, 2-1-1, Soyamacho,
Kita-ku, Kobe 651-1145 Japan.
E-mail:
yohkoada@u01.gate01.com