NDT Plus 2008 1(Supplement 4):iv36-iv40; doi:10.1093/ndtplus/sfn122
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Dialysate as food as an option for automated peritoneal dialysis
Hoey L. Tjiong,
Roel Swart,
Jacobus W. Van den Berg and
Marien W. Fieren
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Correspondence: M. W. J. A. Fieren, Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Tel: +31107040704; Fax: +31107033324; E-mail: m.fieren{at}erasmusmc.nl
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Abstract
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Protein-energy malnutrition is frequently found in dialysis
patients. Many factors play a role in its development including
deficient nutrient intake as a result of anorexia. Peritoneal
dialysis (PD) solutions containing a mixture of amino acids
and glucose in an appropriate ratio could serve as a source
of food. The authors of this article found that such a dialysis
solution when administered to fasting patients who were on nightly
automated peritoneal dialysis (APD), as part of a regular dialysis
schedule, induced an acute anabolic effect. Also in PD patients
in the fed state, dialysis solutions containing both amino acids
and glucose were found to improve protein metabolism. It appears
that the body responds similar to intraperitoneal and oral amino
acid:dialysate as food. Like dietary proteins, intraperitoneal
amino acids can bring about generation of hydrogen ions and
urea as a result of oxidation. No rise of serum urea levels
was found and serum bicarbonate remained within the normal range
when a total buffer concentration of 40 mmol/L in the mixture
was used. The use of this approach may be an option for PD patients
who cannot fulfil dietary recommendations.
Key Words: amino acid dialysate • malnutrition • metabolic acidosis • peritoneal dialysis
Received for publication February 19, 2008. Accepted for publication June 19, 2008.
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Introduction
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Protein-energy malnutrition (PEM) is frequently found in patients
with chronic renal failure and is reported to occur in
40% of
dialysis patients [
1,2]. Besides inadequate intake of proteins
and calories, various other factors are involved in the development
of PEM in patients with renal failure including acidosis, insulin
resistance and uraemic toxins [
3]. With haemodialysis, loss
of amino acids via dialysate may amount to 10 g per dialysis
session, whereas with peritoneal dialysis (PD), protein loss
in infection free patients is
5–10 g per 24 h in addition
to a loss of 2–4 g of amino acids. In the past few years,
the role of inflammation has been in the spotlight. A strong
association has been found between malnutrition, inflammatory
parameters and cardiovascular mortality [
4–7]. It is poorly
understood which pathophysiological mechanisms underlie this
connection. Many strategies have been proposed to improve dietary
nutrient intake in PD patients, but actual protein intake is
frequently below the recommended amount of 1.2 g/kg body weight.
In continuous ambulatory PD (CAPD) patients, amino acid containing
dialysate has been used to compensate for a low dietary protein
intake and peritoneal loss of amino acids and proteins [
8–13].
Till date, convincing clinical benefits have not been demonstrated
unequivocally although amino acids containing dialysis solutions
may lead to a significant increase in serum urea levels and
metabolic acidosis. Currently, amino acid dialysates are not
widely used for the improvement of nutritional status or as
supplement to food intake. It has been generally recommended
to use amino acid dialysate together with a meal containing
enough calories. Lately, it has been shown convincingly that
simultaneous ingestion of calories is really of utmost importance
to obtain an optimal anabolic effect of intraperitoneal amino
acids [
14]. However, anorexia may restrain patients from taking
enough calories together with intraperitoneal amino acids. Recently,
the authors could show that in patients on nightly automated
peritoneal dialysis (APD), a dialysis solution that contains
a mixture of amino acids and glucose, as part of a regular dialysis
schedule, induced an acute anabolic effect [
15]. In that study,
the proportion of energy and protein given via dialysate varied
between 160 and 340 kcal/gN although the western diet contains
150–200 kcal/gN. Taken together, these findings suggest
that the body's response to the amino acid–glucose dialysis
solution is similar to food; this article is a discussion on
‘dialysate as food’. In the next sections, a more
detailed discussion is made on whether this concept could make
sense as nutritional support in clinical practice. First, the
role of diet and inflammation in the nutritional status is dealt
with.
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How much protein does the patient on PD need?
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According to the Kidney Diseases Outcomes Quality Initiative
(DOQI) guidelines, recommended daily dietary protein intake
(DPI) should be at least 1.2 g/kg/day for PD patients [
16].
This target is based on nitrogen balance studies in clinically
stable patients assuming that the intake is within the safe
limit in 97.5% of the population [
17,18]. Many patients, however,
have a neutral or positive nitrogen balance with a DPI of 1.0
g/kg/day and some patients even at a value as low as 0.7 g/kg/day
[
18]. Various studies have shown that actual DPI in many PD
patients is <1.2 g/kg/day even though these patients usually
receive diet counselling. The European Best Practice Guideline
working group on PD allows for a lower DPI target (>1.0 g/kg/day)
if the patient remains in a stable nutritional status. Poor
appetite is central to low intake of proteins and energy. Nutrient
intake is closely correlated with the nutritional status, comorbid
conditions, inflammatory parameters (see the section on inflammation)
and the stage of renal insufficiency [
19]. Pro-inflammatory
cytokines such as TNF
and IL-1β that are known to be implicated
in anorexia and cachexia may be the connecting link.
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Malnutrition, inflammation, atherosclerosis and risk of death
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In various epidemiological studies of dialysis, a strong association
of PEM, inflammation and increased risk of morbidity and mortality
has been found [
4,5,
19]. Various factors including volume overload,
comorbid conditions such as infections, atherosclerosis and
decreased clearance of pro-inflammatory cytokines and glucose
degradation products may contribute to an inflammatory state
in end-stage renal disease (ESRD). Of note, atherosclerosis
itself is an inflammatory process, which may deteriorate further
by infections and other inflammatory conditions, as frequently
found in dialysis patients [
20–22]. Several authors argue
that PEM is the result of inflammation and is a secondary marker
rather than the cause of poor outcome. It is suggested that
PEM without inflammation has only minor harmful effects on outcome.
However, associations, as found in cross-sectional epidemiological
studies, cannot be simply explained in terms of cause and effect.
There is evidence to suggest that inflammation, whatever its
cause, may not be the sole explanation of PEM in ESRD, as suggested
by imprecise association of several nutritional and inflammatory
parameters [
6]. Preliminary data suggest that PEM may independently
promote and increase the risk of clinical illness, leaving room
for the viewpoint that part of the association of PEM and poor
outcome is because of deficient nutrient intake as a result
of anorexia [
6]. Further research is required to elucidate the
pathophysiological mechanisms underlying the aforementioned
associations. To assess the relative contribution of nutrient
intake to outcome, interventional studies including large groups
of patients are needed, selected on the basis of nutritional
status, DPI and inflammatory parameters.
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Amino acid dialysis solutions in CAPD
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To improve the nutritional status in patients on CAPD, glucose
in PD solutions was replaced with amino acids. Using a 1.1%
amino acid solution ultrafiltration is similar to a 1.36% glucose
solution. During a dwell of 4–6 h,
80% of the amino acids,
that is 18 g, are absorbed using a dwell volume of 2 L [
14].
Currently, the commercially available solutions (Nutrineal®)
are composed of a mixture of all essential amino acids and six
nonessential amino acids, three of which are considered to be
essential for ESRD patients. Various studies have been performed
to investigate the clinical effectiveness. These studies differed
in their design, including patient selection, DPI, nutritional
status and duration of follow-up although different nutritional
parameters were used as endpoint [
8–13,
23]. Although in
some studies improvement was found according to selected parameters,
overall there was no consistent amelioration of nutritional
status. In a prospective-controlled interventional study, it
was found that 1–2 bags of a 1.1% amino acid solution
induced a significantly positive nitrogen balance [
24]. In this
study, malnourished PD patients were included who were ingesting
1.0 g protein/kg/day or less, whereas during the study, the
patients were fed a constant diet containing 0.8 g protein/kg/day
and 28 kcal/kg/day energy. The amino acid solutions were exchanged
in the postprandial state. It is really of utmost importance
that intraperitoneal administration of amino acids is accompanied
by simultaneous intake of calories, as was convincingly shown
by Delarue [
14] who compared the effects of intraperitoneal
amino acids with and without consuming a meal composed of carbohydrates
and lipids in CAPD patients. The amino acids stimulated protein
synthesis and the oral calories induced an inhibition of protein
breakdown (i.e. proteolysis) thereby reinforcing the positive
effects of the amino acids solutions on protein balance. In
this study, oral energy and absorbed intraperitoneal amino acids
were given in a proportion of
200 kcal/gN. The normal western
diet contains energy and proteins in a proportion of 150–200
kcal/gN. Anorexia, however, may restrain patients from taking
enough calories simultaneously with intraperitoneal amino acids.
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Combined amino acids and glucose-containing solutions in APD
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Considering that the utilization of intraperitoneal amino acids
could be optimized by giving them simultaneously with glucose,
the hypothesis that in patients who are on nocturnal APD, a
dialysis solution that contains a mixture of amino acids and
glucose, as part of a regular dialysis schedule, could improve
protein metabolism was put forward. In a randomized crossover
study, it could be seen that the mixture of amino acids and
glucose induced an acute anabolic effect on protein metabolism
because of the combined effect of stimulation of protein synthesis
and inhibition of protein breakdown [
15]. Apparently, the body's
response to the administration of intraperitoneal amino acids
is similar to food. The acute changes in protein metabolism
were studied by primed constant infusion of
13C-leucine. Whole
body protein (WBP) turnover, oxidation, synthesis and breakdown
(i.e. proteolysis) were determined by measuring at isotopic
steady state plasma stable isotope enrichment and
13CO
2 production.
Using this sophisticated technique, the protein gain was estimated
at
13 g of protein during a nightly APD session, which is amply
sufficient to compensate for protein losses via dialysate. The
results of the 24-h nitrogen balance studies showed a tendency
towards improvement in nitrogen retention. The studies were
performed in the fasting state while intraperitoneal amino acids
were given in a fixed amount of 27 g, of which
40–50%
was absorbed. The proportion of energy and protein given via
dialysate varied between 160 and 340 kcal/gN. As a supplement
to deficient nutrient intake, an amount of 13 g of absorbed
amino acids is relatively modest and may be inadequate if DPI
is far below the targets. The question arises as to whether
more intraperitoneal amino acids, for example, a double amount,
could be given within the scope of this concept. The optimal
energy-to-protein ratio is unknown and remains to be determined.
If a ratio of 100 kcal/gN or more is to be assumed, per
54 g of amino acids (2 bags of 2.5 L of a 1.1% solution) 216
g of glucose should be given. This can be achieved roughly when
equal volumes of 1.1% amino acid and 3.86% glucose solutions
are mixed with final concentrations of 0.55% and 1.93% for amino
acids and glucose, respectively. Whether this is acceptable
with respect to adverse effects is discussed in a separate section.
The authors also investigated whether this concept could also be utilized for patients in the fed state. This could be of importance for CAPD patients when the amino acids are given in the daytime as a supplement to their (deficient) food intake. Except that the study was performed during the day in patients on CAPD taking liquid food, the study protocol was the same as during nightly APD including the use of an APD cycler. It could be seen that even in the fed state, intraperitoneal amino acids can make an extra contribution to protein synthesis [25]. Furthermore, similar to intraperitoneal amino acids, feeding itself acted almost exclusively on protein synthesis rather than inhibiting protein breakdown thereby corroborating the concept of ‘dialysate as food’. A two-compartment bag system could make this approach feasible for CAPD patients.
Further, the effects of combined amino acids and glucose solutions on fractional albumin synthesis rate (FSR-albumin) were studied. It was found that neither intraperitoneal amino acids nor food induced a statistically significant stimulation of FSR-albumin. In contrast, both the amino acids/glucose mixture and food exerted a significantly stimulating effect on whole body protein synthesis (WBPS) [26]. These findings demonstrate a differential effect of both oral and intraperitoneal amino acids on the synthesis rates of albumin and WBP. As muscle protein synthesis contributes substantially to WBPS, the stimulating effect of amino acids on WBPS may be attributed to a large extent to increased muscle protein synthesis consistent with previous reports [27]. However, it should be mentioned in this context that the most marked stimulation of albumin synthesis by protein supply has been found under protein-depleted conditions [28]. This study was conducted in a small, relatively stable and well-nourished population of CAPD patients.
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Adverse effects of intraperitoneal amino acids
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Several studies on CAPD patients have shown that the use of
amino acid dialysate is accompanied by acidaemia occurring within
1–4 weeks after starting the daily use of these solutions
[
8,
24]. It is caused by metabolism of the sulfur-containing
amino acid methionine and the cationic amino acids arginine
and lysine-HCl. Therefore, the concentration of these amino
acids was decreased in the newer commercially available dialysis
solutions (Nutrineal®). Despite the use of dialysate with
lower concentrations of aforementioned amino acids, a trend
to acidosis has still been described especially when two bags
per day were used giving reason for concern [
24,
29]. Therefore,
it is generally recommended to use no more than one bag of a
1.1% amino acid solution per day. It should be noted in this
respect that dietary proteins are the main source of the generation
of H
+ ions (protons) by hydrolysis of dietary phosphate existing
as H
2PO
4– and by oxidation of the sulfur-containing amino
acids methionine and cysteine as well as the cationic amino
acids arginine and lysine, which come available by food intake
or endogenously by proteolysis [
30,31]. On the other hand, the
metabolism of anionic amino acid glutamate and aspartate generates
alkali. Collectively, this results in a net hydrogen ion production
of 1–2 mEq/kg/day in healthy adults on a normal Western
diet. Increasing intake of dietary proteins along with organic
H
2PO
4– results in production of increasing amounts of
hydrogen ions that have to be removed by the kidney to maintain
acid base homeostasis. Halperin estimated that in a diet containing
120 g of proteins (note: 100 g of beef contain 20 g of protein),
72 mEq and 138 mEq of H
+ are generated by metabolism of sulfur-containing
amino acids and cationic amino acids, respectively [
32]. On
the other hand, by metabolism of glutamate and aspartate, 100
mEq of H
+ are removed, whereas the oxidation of various other
dietary organic anions removes additionally 60 mEq of H
+. This
would imply that net acid production by amino acids in such
a diet is
210–100 mEq = 110 mEq. Organic H
2PO
4– has not been taken into account as a source of acid production
in the calculations. In patients with renal failure, quantity
and class of phosphate binders complicate the role of phosphate
in acid generation [
33]. Table
1 shows that the estimated hydrogen
ion generation by absorbed amino acids in 2.5 L of a 1.1% amino
acid solution (
13.5 g) is
33 mEq if the quantity of absorbed
amino acids is completely oxidized. The fact that net acid production
by the current intraperitoneal amino acids solution is higher
compared with the same amount of dietary protein can be largely
explained by the absence of the alkali-generating glutamate
and aspertate in the dialysis solution. On the other hand, lactate
and bicarbonate are added to dialysis solutions for the provision
of alkali [
34]. In the fasting state study, a slight decrease
of serum bicarbonate concentrations with amino acids containing
dialysate was found, but the bicarbonate levels remained within
the normal range when dialysis solutions containing a 40 mmol/L
buffer was used. Furthermore, substantial part of the supplied
amino acids was not oxidized but was utilized for anabolism
as shown in the whole-body protein turnover (WBPT) studies and
this may have resulted in a low production of hydrogen ions
and urea as well. These findings may suggest that intraperitoneal
amino acids, insofar as they are given to supply the deficit
of protein intake, bring about only a limited increase in the
generation of H
+ ions and urea. In addition, the findings of
this study suggest that metabolic acidosis could be prevented
even with higher doses of intraperitoneal amino acids when the
concentration of buffer in the mixture of amino acids and glucose
containing dialysis solutions is 40 mmol/L.
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Feasibility in clinical practice
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The intraperitoneal administration of amino acids combined with
glucose can take place as part of a regular dialysis schedule
in APD patients with the cycler regulating the mixing of amino
acids and glucose. Applying an ‘empty bag procedure’
mixing occurs from the first cycle onward. The dialysis procedure
that is described in detail elsewhere is easy to perform at
home [
15]. Developments in software could further simplify the
practice of the dialysis procedure and could make the application
of the concept of ‘dialysate as food’ more versatile.
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Conclusion
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Automated peritoneal dialysis with a mixture of amino acids
and glucose brings about an acute improvement of protein metabolism.
Such a response of the body to intraperitoneal amino acids is
similar to food-‘dialysate as food’. Like dietary
protein, intraperitoneal amino acids can bring about the generation
of hydrogen ions and urea. No rise of serum urea levels was
found with the amount of amino acids given in this study and
serum bicarbonate levels remained within the normal range when
a buffer concentration of 40 mmol/L in the mixture of amino
acids and glucose was used. The use of this approach may be
an option for PD patients who cannot fulfil dietary recommendations.
APD is very suitable to individualize the dose of intraperitoneal
amino acids. The procedure is easy to perform at home. Developments
in software could make the application of this approach more
versatile. Long-term clinical trials are required to evaluate
the effects on morbidity and mortality.
Conflict of interest statement. None declared.
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Abstract
Introduction