THE CHOICE OF DIALYSIS SOLUTIONS IN PEDIATRIC
CHRONIC PERITONEAL DIALYSIS: GUIDELINES BY AN
AD HOC EUROPEAN COMMITTEE1
Cornelis H. Schröder
On behalf of the European Pediatric Peritoneal Dialysis Working Group*
Correspondence:
C.H. Schröder, MD, PhD
Dept. of Pediatric Nephrology
Wilhelmina Children University Hospital
POB 85090
3508 AB Utrecht
The Netherlands
Tel.: +31.30.2504001
Fax: +31.30.2505349
E-mail:
c.h.schroder@wkz.azu.nl
c.hschroder@freeler.nl
*The European Pediatric Peritoneal Dialysis Working Group:
A. Edefonti, I Clinici di Perfezionamento, Milan, Italy
M. Fischbach, Hôpital de Hautepierre, Strasbourg, France
G. Klaus, University of Marburg, Marburg, Germany
K. Rönnholm, University of Helsinki, Helsinki, Finland
F. Schaefer, University of Heidelberg, Heidelberg, Germany
E. Simkova, University Hospital Motol, Prague, Czech Republic
D. Stefanidis, A&P Kyriakou Childrens Hospital, Athens, Greece
V. Strazdins, University of Riga, Riga, Latvia
J. Vande Walle, University of Ghent, Ghent, Belgium
A. Watson, Nottingham City Hospital, Nottingham, United Kingdom
A. Zurowska, University of Gdansk, Gdansk, Poland
1
Published in Perit Dial Int 2001;21:568-574
1
Abstract
Objective: To provide guidelines on the choice of dialysis solutions in children on chronic
peritoneal dialysis.
Setting: European Pediatric Peritoneal Dialysis Working Group (EPPWG)
Data source: Literature on the application of peritoneal dialysis solutions in children
(evidence) and discussions within the group (opinion).
Conclusions: Glucose is the standard osmotic agent for peritoneal dialysis in children
(evidence). The lowest glucose concentration needed should be used (opinion). Low calcium
solution (1.25 mmol/L) should be applied, wherever possible, with careful monitoring of
parathyroid hormone levels (opinion). The use of amino acids containing dialysis fluids can
be considered in malnourished children, although aggressive enteral nutrition is preferred
(opinion). There is insufficient evidence documenting the efficacy of intraperitoneally
administered amino acids (evidence). Polyglucose solutions are a welcome addition to the
treatment of children on NIPD, when ultrafiltration and/or solute removal are insufficient
(evidence). However, in the absence of any reported long-term experience in children their
use must be closely monitored (opinion). Bicarbonate would appear to be the preferred buffer
for peritoneal dialysis in children, but more in vivo studies are required before it replaces the
present lactate containing solutions (evidence/opinion).
Running title: PD fluids in children
Key words:
peritoneal dialysis solutions, children, glucose, calcium, amino acids,
icodextrin, bicarbonate.
2
Commencing chronic peritoneal dialysis in an individual child requires the choice of
an appropriate dialysis solution from the large number that are available. The choice is usually
straightforward in a child commencing dialysis, but the choice of solution is more important
and difficult in the case of patients with complications, such as ultrafiltration failure and
malnutrition. In addition to the traditional glucose solutions there are now a number of
different osmotic agents and buffers available.
The European Pediatric Peritoneal Working Group (EPPWG) was established in 1999
by pediatric nephrologists with a major interest in peritoneal dialysis and has already initiated
guidelines on commencing elective chronic peritoneal dialysis [1]. One of the functions of the
group is to establish expert guidance in important clinical areas associated with peritoneal
dialysis in conjunction with other members of the multidisciplinary team. These guidelines
were initiated and discussed at meetings of the group and developed by e-mail discussion to
develop consensus of opinion based upon cumulative clinical experience and reported studies.
This paper will discuss the advantages and disadvantages of the dialysis solutions available
and highlight any reported pediatric experience, and provides recommendations for the
choice.
Attempts have been made to base these recommendations on evidence obtained from
the published literature. It should be kept in mind, however, that the number of available
pediatric studies in this field and the size of these studies does not allow development of
evidence-based recommendations on a firm basis. Multicenter studies on a larger scale have
to be conducted to provide more evidence for the recommendations.
Osmotic agents
3
Glucose
From the start of peritoneal dialysis as a therapy for renal failure glucose has been
used as the osmotic agent. Table I gives information on the composition and some properties
of conventional dialysis solutions commonly prescribed. The low pH and the high osmolarity
are prominent characteristics. The high osmolarity of conventional dialysis solutions is caused
by the glucose content. The low pH of these solutions will be discussed later in this paper.
The high glucose concentration gives rise to a high glucose absorption, adding calories to the
patient on the one hand, but causing hyperlipidemia and hyperinsulinemia on the other.
A large number of studies, both in vitro and in vivo, have been published proving
detrimental effects of these solutions on the (intra)peritoneal cells. These effects have recently
been extensively reviewed by Krediet et al [2]. Mesothelial cells are inhibited with respect to
their proliferation and cytokine production [3-5]. In vitro research demonstrated necrosis of
human monocytes after exposure to dialysis solutions [6].
The high glucose concentration in the dialysis solution leads to irreversible
glycosylation of proteins [7-9]. Subsequently, glucose degradation products and advanced
glycosylation end products are formed, which may contribute to the functional deterioration
of the peritoneal membrane in long-term dialysis [10-13]. These products have been shown to
affect cellular growth and induce functional changes in monocytes and neutrophils.
In order to avoid the possibility of functional deterioration of the peritoneal membrane
due to the high glucose content and low pH of these solutions, the solution with the lowest
glucose should be used in daily practice. Regular assessment of both dietary fluid intake and
urinary output should be performed. In infants high glucose concentrations can rapidly lead to
dehydration and their use needs careful supervision.
4
Because of the unfavorable properties of glucose as an osmotic agent a number of
alternative osmotic agents have been studied and will be discussed later. Experience with
some of these solutions is limited, particularly with respect to specific pediatric data.
A few remarks have to be made on the calcium content of the dialysis fluid. The
standard calcium concentration is 1.75 mmol/L (Table I). The use of dialysis solutions
containing this concentration frequently leads to hypercalcemia if patients are simultaneously
treated with Ca-containing phosphate binders and vitamin D analogs. Therefore, low calcium
dialysis solutions (1.25 mmol/l) have been developed, aiming to allow higher dosage of oral
phosphate-binding calcium salts, and to minimize hypercalcemia. Although the experience in
children with these solutions is very limited [14], the results and the experience from adult
studies confirm this theory [15-17]. On the contrary, it should be remembered that in adult
patients there is a certain risk that severe secondary hyperparathyroidism with long-term lowcalcium therapy will develop, even if normocalcemia is obtained [18-20]. In children a
slightly positive calcium balance might be needed because of the growing skeleton. Although
there is no specific pediatric literature on this topic, it can be assumed that this may also occur
in children.
Recommendation
Glucose is the standard osmotic agent for peritoneal dialysis in children. (evidence) The
lowest glucose concentration needed should be used. (opinion) Low calcium solution (1.25
mmol/L) should be applied, wherever possible, with careful monitoring of parathyroid
hormone levels at least every 3 months. (opinion)
Amino acids
5
Amino acids, administered once daily for a 4-6 hour dwell, are claimed to supply
nutrition to dialysis patients and to compensate for peritoneal protein losses [21-26]. Although
in these studies statistically significant rises in serum albumin, pre-albumin, transferrin, and
mid arm muscle circumference have been reported, it is still to be established that amino acids
contribute to an improved long-term nutritional status. Conversely, amino acids tend to
worsen acidosis and to increase urea load. The composition of the only presently available
preparation is given in Table II. There are a number of publications describing the experience
with amino acid solutions in children [27-31]. The most extensive studies have been
performed by Canepa and colleagues. In a study in 8 children for a period of 6 months, in
which the amino acid solution was mixed with a glucose solution in a continuous peritoneal
dialysis (CPD) regimen, an improvement of anthropometric parameters, like mid arm
circumference and weight-for height percentile occurred [30]. There were no modifications in
blood urea nitrogen levels, nor in serum levels of total proteins and albumin. The authors
concluded that the main advantages of administering supplemental amino acids by the
peritoneal route are the good compliance without modification of the normal dialysis
procedure, and the fact that the supplemental nitrogen by amino acids carries no additional
phosphorus. Especially this latter property seems to be important, since phosphate control in
children is often a problem, partly caused by the relatively high protein intake. Amino acid
dialysis solutions are relatively expensive. Whenever possible, the enteral route is preferred to
correct malnutrition.
Recommendation
The use of amino acid containing dialysis fluids can be considered in malnourished children,
although aggressive enteral nutrition is preferred. (opinion) There is insufficient evidence
documenting the efficacy of intraperitoneally administered amino acids. (evidence)
6
Polyglucose
Polyglucose solutions have been extensively studied both in adults and in children.
The commercially available polyglucose solution (icodextrin 7.5%) contains glucose
polymers with an average molecular weight of 16,200 D. The composition and some of the
properties are given in Table III. Because of the low adsorption of these large-molecular
weight substances ultrafiltration is sustained making icodextrin very suitable for long-time
dwell periods [32-34]. In adult patients improved ultrafiltration during a day-time dwell was
obtained with icodextrin compared to glucose 1.36% [35]. De Boer et al. studied the effects of
icodextrin in 11 children who were being treated with a NIPD (nightly intermittent peritoneal
dialysis) regimen [36]. Icodextrin was compared with glucose 1.36% and glucose 3.86% for a
12-hour dwell period. Net ultrafiltration obtained with the icodextrin solution was similar to
that obtained with the glucose 3.86% solution, and significantly higher than that observed
with the glucose 1.36% solution. In these children the daily administration of icodextrin added
a mean of 0.52 (standard deviation 0.07) to weekly KT/V urea, because of the longer time on
dialysis. The sustained but slow ultrafiltration is illustrated by the absence of a drop of
dialysate sodium concentration in the group treated with icodextrin, a phenomenon normally
occurring in patients treated with 3.86% glucose, who are presumed to have a normally
functioning peritoneal membrane [37,38]. In the 4-hour peritoneal equilibration test net
ultrafiltration is much lower than using a glucose 3.86% glucose solution [39].
The potential toxicity of icodextrin solutions has been studied both in adults and in
children and has provided similar results [32,36,40]. In a study in which icodextrin was
7
prescribed for the daytime dwell in children on NIPD for 6 weeks, icodextrin blood levels
rapidly increased to a steady state reached after 2 weeks [36]. Two weeks after the
discontinuation of the study icodextrin was not detectable in the blood anymore. Blood levels
of the main metabolites of icodextrin (maltose, maltotriose, and maltotetraose) followed a
similar pattern. Concentrations were identical to those measured in adult patients [32,40]. In
some patients hypersensitivity reactions towards icodextrin have been reported [41-43]. In the
one pediatric study a hypersensitivity reaction was observed in one out of 11 patients [36]. In
adult patients long-term experience with icodextrin is increasing; in children this is still very
limited.
Recommendation
Polyglucose solutions are a welcome addition to the treatment of children on NIPD, when
ultrafiltration and/or solute removal are insufficient. (evidence) However, in the absence of
any reported long-term experience in children their use must be closely monitored. (opinion)
Other osmotic agents
Although literature is available on the use of glycerol [44-48] and oligopeptides [4951] as an osmotic agent, their application is still considered experimental. Dialysis fluids
containing these agents are not commercially available and hence they are not recommended
for application in children.
Buffers
8
Acetate
Acetate, which was the standard buffer in the early peritoneal dialysis solutions, has
been completely abolished because of its strong association with the development of
sclerosing peritonitis [52,53].
Lactate
Lactate is currently the standard buffer applied in dialysis solutions. Lactate was
chosen because solutions containing mixtures of bicarbonate, calcium, and glucose cause the
formation of insoluble calcium salts. Under normal conditions lactate is regularly
metabolized, but is stimulates collagen synthesis by fibroblasts. On the other hand sterilizing
these solutions at physiological pH leads to caramelization of glucose. Therefore pH of
standard peritoneal dialysis solutions varies between 5.0 and 6.5 (Table I).
Bicarbonate
The number of reports using bicarbonate as a more physiological buffer is increasing.
This can only be done if a double bag is created, one side containing glucose and calcium, and
the other containing sodium bicarbonate. These bags have to be mixed shortly before
administration. Bicarbonate buffered solutions have a more physiological pH (7.0-7.6) than
lactate-based solutions (5.5-6.5). The composition and some of the properties of three
commercially available bicarbonate or bicarbonate/lactate dialysis solutions is given in Table
IV.
Most of the studies performed with these solutions report positive results, when
compared to lactate-buffered dialysis solutions [54-56]. In vitro studies showed markedly
9
better preserved function of both macrophages and human peritoneal mesothelial cells [5761]. An effective control of acid base balance is demonstrated by several in vivo studies [6266]. An interesting property of this solution is the lower incidence of infusion pain [67].
Infusion pain is generally agreed to be due to the acidity of the conventional solutions. Studies
in adult patients demonstrate a clear reduction of infusion pain and discomfort. This property
is particularly important for some children. Although there is experience in the pediatric
dialysis centers using custom-made bicarbonate dialysis solutions in cases with lactate
acidosis, no papers have been published on the chronic use and effects of bicarbonate-based
peritoneal dialysate [68]. It is known that inflow pain can be treated by pH adjustment of the
dialysis fluid with bicarbonate [69]. Since in pediatric dialysis dwell times usually are very
short, the application of a pH-neutral, bicarbonate-based solution seems to be indicated. The
pediatric experience is only published in abstract-form [70,71]. In one study 5 children were
switched from lactate to bicarbonate containing dialysis solutions [70]. The duration of the
study was not mentioned. No differences with respect to adequacy, ultrafiltration, or
laboratory values were established for the two periods, but there was an important decrease in
abdominal pain during the filling phase, with a concomitant lower intraperitoneal pressure.
The second study was devoted to the characteristics of bicarbonate dialysis fluid in a
peritoneal equilibration test [71]. In 25 children peritoneal fluid kinetics and solute transport
were similar to the results obtained using traditional lactate dialysis fluid. Intraperitoneal pH
was significantly lower during the first hour with the latter dialysis fluid. More studies in
pediatric patients are urgently needed.
10
Recommendation
Bicarbonate would appear to be the preferred buffer for peritoneal dialysis in children, but
more in vivo studies are required before it replaces the present lactate based solutions.
(evidence/opinion)
Conclusion
Since the preferred treatment modality in children is NIPD, dwell times are usually
short [72]. This makes the application of a pH-neutral dialysis solution for the standard
nightly prescription highly desirable. If ultrafiltration and/or KT/V urea are insufficient using
this regimen, the addition of a long day-time dwell with polyglucose solutions should be
considered. The place of amino acid containing dialysis fluids in pediatric peritoneal dialysis
still has to be determined.
11
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19
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20
Table I: Composition of glucose-containing dialysis solutions.
Dianeal® PD1
CAPD 2-4®
Gambrosol trio 10®
(Baxter)
(Fresenius)
Sodium
132
134
132
mmol/l
Calcium
1.75
1.75
1.75
mmol/l
Magnesium
0.75
0.5
0.25
mmol/l
Chloride
102
103.5
96
mmol/l
Lactate
35
35
40
mmol/l
Glucose
13.6-38.6
15-42.5
15.2-38.8
g/l
Osmolality
340-483
358-512
353-492
mOsm/l
PH
5.5
5.5
6.5
(Gambro)
21
Table II: Composition of amino acid 1.1% dialysis solution (Nutrineal®, Baxter)
Essential Amino Acids
Valine
Leucine
Isoleucine
Methionine
Lysine
Threonine
Phenylalanine
Tryptophan
Histidine
1.39
1.02
0.85
0.85
0.76
0.65
0.57
0.27
0.71
g/l
g/l
g/l
g/l
g/l
g/l
g/l
g/l
g/l
Non-Essential Amino Acids
Arginine
Alanine
Proline
Glycine
Serine
Tyrosine
1.07
0.95
0.60
0.51
0.51
0.30
g/l
g/l
g/l
g/l
g/l
g/l
Electrolytes
Sodium
Calcium
Magnesium
Chloride
Lactate
132
1.25
0.25
105
40
mmol/l
mmol/l
mmol/l
mmol/l
mmol/l
Osmolarity
365
mOsm/l
PH
6.7
22
Table III: Composition of polyglucose (icodextrin 7.5%) dialysis solution(Extraneal®,
Baxter).
Sodium
133
mmol/l
Calcium
1.75
mmol/l
Magnesium
0.25
mmol/l
Chloride
96
mmol/l
Lactate
40
mmol/l
Icodextrin
75
g/l
Osmolarity
284
mOsm/l
PH
5.2
23
Table IV: Composition of bicarbonate-containing dialysis solutions.
Physioneal®
Stay●Safe®
(Baxter)
(Fresenius)
Sodium
132
134
mmol/l
Calcium
1.25
1.75
mmol/l
Magnesium
0.25
0.5
mmol/l
Chloride
95
104.5
mmol/l
Bicarbonate
25
34
mmol/l
Lactate
15
0
mmol/l
Glucose
13.6-38.6
15-42.5
g/l
Osmolarity
344-483
358-511
mOsm/l
pH
7.0-7.4
7.0-7.6
24