Peritoneal Dialysis Solutions

14

Elizabeth Harvey

Introduction
The peritoneal dialysis solution (PDS) is the cornerstone of peritoneal dialysis (PD), responsible
for both fluid removal and metabolic control. As
eloquently stated by Rippe, “the optimal electrolyte composition of a dialysis solution is that
which best serves the homeostatic needs of the
body” [1]. The absolute requirements for a PDS
are a buffer to manage acidosis, an osmotic agent
to produce ultrafiltration (UF), and electrolytes
including sodium, chloride, calcium, and magnesium to maintain homeostasis and prevent metabolic bone disease. Yet more than half a century
since the introduction of PD as a chronic therapy
for replacement of renal function, the ideal PDS
remains elusive. This likely reflects the diverse
nature and diet of patients on PD, the need to customize treatment based on individual peritoneal
transport characteristics, the type of dialysis
(continuous ambulatory peritoneal dialysis
(CAPD) versus automated peritoneal dialysis
(APD)), dwell time, residual renal function, age
and growth requirements, and accumulating data
on the beneficial and harmful effects of PDS
including their interaction with other components
of CKD management [2].

E. Harvey (*)
Hospital for Sick Children, Department of Pediatrics,
University of Toronto, Toronto, ON, Canada

e-mail:

This chapter will review PD solutions including biocompatibility, key composition, specific
solutions, new solutions, and membrane preservation strategies.

Biocompatibility
Increasing length of time on PD has been associated with an increase in small solute transport
and decreased ultrafiltration, both of which are
associated with an increased risk of technique
failure and death. The pathological correlate of
these functional changes was first elucidated by
Williams et  al. in their landmark description of
the changes in the peritoneal membrane associated with uremia and PD.  These changes were
characterized by loss of the mesothelial layer,
marked increase in the thickness of the submesothelial compact collagenous zone, and a progressive hyalinizing vasculopathy, with worsening of
severity correlating with duration of PD [3]. UF
failure was associated with increased blood vessel density.
These changes were attributed in part to the
use of “bio-incompatible” PD fluids, characterized by low pH (<6), high lactate concentration
(35–40  mmol/L), high osmolarity, high glucose
concentration, and high glucose degradation
products (GDPs) [4]. This ushered in the era of
“biocompatible” fluids including neutral pH
solutions, alternate osmotic agents such as

© Springer Nature Switzerland AG 2021
B. A. Warady et al. (eds.), Pediatric Dialysis, />
229



230

i­codextrin, bicarbonate dialysate, and low GDP
solutions.
Glucose Degradation Products  GDPs are generated during heat sterilization and prolonged
storage of glucose containing solutions [5, 6].
GDPs impair mesothelial cell function, stimulate
local cytokine production, and are thought to be
key contributors to the peritoneal alterations seen
with long-term PD [6]. GDPs bind to proteins
and lipids to produce advanced glycation end
products (AGEs) which in the peritoneum contribute to peritoneal fibrosis. GDPs are rapidly
absorbed across the peritoneal membrane, resulting in elevated levels of AGEs in patients with
renal failure, and are implicated in complications
of renal failure such as vasculopathy and amyloidosis [7].

E. Harvey

Table  14.1), also made possible by the multichamber bag. With bicarbonate-based solutions,
calcium and magnesium must be separated from
bicarbonate during heating and storage to prevent
precipitation of calcium carbonate and magnesium carbonate.

The production of GDPs can be reduced in an
acid solution, and the early lactate-based PDS,
many of which are still in use, have an unphysiological pH of 5.2 which may be associated with
infusion pain. A breakthrough in manufacturing
was the development of the multichamber bag
which allowed separation of the buffer source
(lactate and/or bicarbonate) from the glucose

which could be in an acid milieu, resulting in
lower GDP production during sterilization [6].
Neutral pH of the whole solution was achieved
by mixing the two compartments just prior to
instillation. However, even solutions considered
to be low in GDPs have significant variability in
the GDP concentrations, hampering interpretation of clinical trial results [8]. Two chamber
bags are most commonly available, with
Gambrosol Trio™ (Fresenius Med Corp) utilizing a three-chamber bag which allows for three
different glucose concentrations from a single
bag, depending on which of the three chambers
are mixed together before infusion.

Clinical
Data
with
Biocompatible
Solutions  Unfortunately, multiple studies on
these “biocompatible” solutions with neutral pH
and low GDPs have yielded conflicting results on
clinically relevant outcomes, most likely due to
study design, duration, and power [9, 10].
Biocompatible solutions have been associated
both with an increased risk of peritonitis and
shorter time to the first peritonitis episode [11,
12] and a lower rate of peritonitis and longer time
to the first peritonitis [13, 14]. In meta-analyses
and systematic reviews, several themes have
emerged, namely, better preservation of residual
renal function especially urine volume and less

inflow pain [12, 15–20]. Several studies have
shown that biocompatible solutions have been
associated with lower ultrafiltration and increased
peritoneal solute transport at initiation, which
stays stable over time, compared to deterioration
in ultrafiltration and increasing solute transport
over time with conventional PDS (cPDS) [13,
14]. Conversely, two studies of prevalent adult
patients switched to a low GDP solution have
shown decreased ultrafiltration and overhydration compared to conventional solutions [21, 22]
but with lower blood C-reactive protein (CRP)
values in the low GDP solution group. It has been
speculated that the preservation of residual renal
function seen with the low GDP solutions may in
part be due to overhydration [23]. Overall, while
no harm has been attributed to these newer solutions, there has been no improvement in patient
or technique survival demonstrated to date [8, 10,
15, 24, 25].

Neutral pH Solutions  The concern that pH was
a factor not just in GDP production, but in damage to the peritoneal membrane, as well as clinical consequences of pain on infusion, led to the
development of neutral pH solutions such as
Physioneal™, Balance™, and Bicavera™ (see

Encapsulating sclerosing peritonitis (EPS) is a
devastating complication of long-term peritoneal
dialysis [26] (see Chap. 39). Interestingly, both
Japanese [27] and Dutch [28] registries demonstrate a reduced incidence of EPS over the last
decade. Whether this is due in part or wholly to



Dextrose
1.5%
2.5%
4.25%
Dextrose
0.5%
1.5%
2.5%
4.25%
Glucose
1.5%
2.3%
4.25%
Glucose
1.5%
2.3%
4.25%
Glucose
1.5%
2.3%
4.25%

PD4™ Baxter 1 chamber

Bicavera™ Fresenius 2
chambers

Balance™ Fresenius
1.75 mmol/l Ca 2 chambers


Balance™ Fresenius
1.25 mmol/l Ca 2 chambers

PD101™ Baxter 1 chamber

Osmotic
agent
Icodextrin
7.5%
Amino acid
1.1%
Glucose
1.36%
2.27%
3.86%

Solution/manufacturer/
number of chambers
Extraneal™ Baxter 1
chamber
Nutrineal™ PD4 Baxter 1
chamber
Physioneal™ 40 Baxter 2
chambers
6.4
7.4

5.2


5.2

7.0

7.0

7.4
7.4
7.4

0
25
25
25

0
0
0
0
0
0
0
0
0
0
0
0
0
34
34

34

40
15
15
15

40
40
40
35
35
35
35
35
35
35
35
35
35
0
0
0

0.25 (0.5)
0.25 (0.5)
0.25 (0.5)
0.25 (0.5)

0.25 (0.5)

0.25 (0.5)
0.25 (0.5)
0.75 (1.5)
0.75 (1.5)
0.75 (1.5)
0.75 (1.5)
0.5 (1.0)
0.5 (1.0)
0.5 (1.0)
0.5 (1.0)
0.5 (1.0)
0.5 (1.0)
0.5 (1.0)
0.5 (1.0)
0.5 (1.0)

1.25 (2.5)
1.25 (2.5)
1.25 (2.5)

1.25 (2.5)
1.25 (2.5)
1.25 (2.5)
1.62 (3.25)
1.62 (3.25)
1.62 (3.25)
1.62 (3.25)
1.25 (2.5)
1.25 (2.5)
1.25 (2.5)

1.75 (3.5)
1.75 (3.5)
1.75 (3.5)
1.75 (3.5)
1.75 (3.5)
1.75 (3.5)

132(132)
132(132)
132(132)

132(132)
132(132)
132(132)
132 (132)
132 (132)
132 (132)
132 (132)
134 (134)
134 (134)
134 (134)
134 (134)
134 (134)
134 (134)
134 (134)
134 (134)
134 (134)

344
395

483

345
395
484
296
347
397
485
356
399
509
368
401
511
358
401
511

15 G/L
22.73 G/L
42.5 G/L
Glucose
monohydrate
15 G/L
22.73 G/L
42.5 G/L

Bicarbonate
mmol/L

pH
0
5.2

1.25 (2.5)

Lactate
mmol/l
40

132 (132)

Mg mmol/l
(mEq/L)
0.25 (0.5)

365

Ca mmol/l
(mEq/L)
1.75 (3.5)

Amino acids
87 mmol/L
Glucose
monohydrate
15 g/L
25 g/L
42.5 g/L
Dextrose

15 g/L
25 g/L
42.5 g/L
Dextrose
5 g/L
15 g/L
25 g/L
42.5 g/L
15 G/L
22.73 G/L
42.5 G/L

Na mmol/l
(mEq/L)
133 (133)

Osmolarity
mOsm/L
284

Osmotic agent
concentration
Icodextrin 75 g/L

Table 14.1  Composition of common PD solutions

(continued)

Low
42a


Low
42a

Low
253a

GDPs
Low

14  Peritoneal Dialysis Solutions
231


Osmotic
agent
Glucose
1.5%
2.5%
3.9%

Osmotic agent
concentration
Glucose
15 G/L
25 G/L
39 G/L

GDP glucose degradation product
a

Mean GDP concentration in μmol/L of 3-deoxyglycosone

Solution/manufacturer/
number of chambers
Gambrosol trio™ 10
Gambro 3 chambers

Table 14.1 (continued)
Osmolarity
mOsm/L
357
409
483

Na mmol/l
(mEq/L)
133
132
131

Ca mmol/l
(mEq/L)
1.79 (3.58)
1.75 (3.5)
1.7 (3.4)

Mg mmol/l
(mEq/L)
0.26 (0.52)
0.25 (0.5)

0.24 (0.48)

Lactate
mmol/l
41
40
39

Bicarbonate
mmol/L
0
0
0
pH
5.5–6.5
5.5–6.5
5.5–6.5

GDPs
Low
65a

232
E. Harvey


14  Peritoneal Dialysis Solutions

more biocompatible PDS cannot be ascertained
at this point.

The longitudinal analysis of the Global Fluid
Study in adults examined the long-term peritoneal solute transport rate (PSTR) in patients
using biocompatible solutions (7.5 years) versus
cPDS (12.8 years) [29] and found a progressive
increase in PSTR over time with cPDS, while
biocompatible solutions were associated with
stability of the PSTR by 2  years. The early
increase in PSTR seen with the biocompatible
solution in the balANZ trial [30] was not seen in
this study, likely reflecting study methodology,
different biocompatible solutions, and timing of
peritoneal equilibration testing [31]. The use of
biocompatible PDS also appeared to attenuate
the elevated PSTR seen during episodes of peritonitis [29], possibly by reducing the severity of
peritonitis as suggested in the balANZ study
[14]. Whether the use of biocompatible solutions
will result in a lower incidence of EPS over time
remains to be seen.
Pediatric Clinical Data  In a prospective study
of 401 children by the International Pediatric
Peritoneal Dialysis Network (IPPN), the use of
biocompatible PDS was associated with a marginal improvement in daily urine output, but did
not reduce the risk of developing oligoanuria
[32]. In a prospective cohort study of 65 children,
the use of neutral pH/low GDP solutions was
associated with higher free water transport compared to acid pH/high GDP solutions [33].
Pathology Studies  In vivo benefit of biocompatible solutions has been suggested by the morphological study of 46 adults (23 biocompatible PDS
and 23 cPDS) matched for time on dialysis [34].
Biocompatible PDS was associated with
improved mesothelial layer integrity and less

hyalinizing vasculopathy. Similarly, another peritoneal morphology study of adults at termination
of PD showed that the use of neutral pH and low
GDP solution was associated with less membrane
fibrosis, less vascular sclerosis, and less AGE
accumulation compared to acidic cPDS [35].
Despite an increase in the number of peritoneal
capillaries, the neutral pH solutions were associ-

233

ated with lower peritoneal equilibration (PET)
scores and preserved UF volumes.
However, the seminal peritoneal morphology
study of children on PD lays waste to the theory
that “biocompatible” PDS preserves the peritoneal membrane and places the focus again on the
osmotic agent, glucose, as the culprit in long-­
term membrane dysfunction [36, 37]. This study
performed a comprehensive analysis of peritoneal biopsies on children with end-stage kidney
disease before commencing PD (90 patients) and
while on PD (82 patients) with control specimens
on 56 children with normal kidney function. It
showed a marked early (6–12 month) increase in
peritoneal blood microvessel density, an increase
in endothelial surface area per peritoneal volume,
and an increase in submesothelial thickness
despite the use of neutral pH solutions with low
GDP concentrations. Multivariate analysis
showed that increasing glucose exposure was
associated with total vessel density. Additionally,
vessel density correlated positively with 2-hour

dialysate-to-plasma (D/P) creatinine and
inversely with 2-hour dialysate-to-dialysate at
time zero (D/Do) glucose on PET and predicted
solute transport at 3 and 6 months. Cluster analysis showed marked angiogenesis in younger children with short PD vintage and submesothelial
fibrosis in older children on long-term PD. While
it is uncertain if these findings are generalizable
to adults, the early, marked peritoneal angiogenesis observed in this study potentially explains
the faster peritoneal transport and lower UF seen
in adult studies using neutral pH and low GDP
solutions [30].

PD Solution Components
pH/Buffer  End-stage renal disease (ESRD) is
characterized by metabolic acidosis. Correction
of this acidosis is a vital component of any renal
replacement therapy including PD. To that end,
PDS must contain a buffer. Early attempts to use
bicarbonate in single-chamber bags led to
­precipitation of calcium carbonate [38]. Acetate
was used initially but was quickly discontinued


234

due to infusion pain, prolonged acidic pH of the
infused solution, peritoneal membrane damage
and loss of UF, systemic alkalosis, and an association with EPS [39–41]. Therefore, solutions
with L-lactate in concentrations of 35–40 mmol/L
with an acidic pH of approximately 5.2 became
widely used. Instillation into the abdomen is

associated with rapid equilibration of the pH in
the abdominal fluid to 7.4 over 10 minutes, followed by a gradual drop in peritoneal lactate due
to diffusion into the blood across the concentration gradient, where it is then metabolized to
bicarbonate. Recent animal studies show that the
neutralization of pH is achieved both by bicarbonate diffusion out of the blood into the PD
fluid and local production of bicarbonate by
peritoneal carbonic anhydrase isoforms, with
bicarbonate transport not mediated by the water
channel aquaporin 1 [42]. Absorbed lactate is
rapidly metabolized via the Krebs cycle or via
gluconeogenesis, and stable chronic dialysis
patients have normal serum lactate levels.
However, during intercurrent illness, lactate levels may become elevated in the absence of
hypoxemia or gut ischemia, precipitating unnecessary investigations [43].
By contrast, a brief randomized crossover
study of 25 children comparing lactate versus
bicarbonate solutions during a 4-hour PET demonstrated a persistently acidic PD fluid up to an
hour of dwell time with the lactate-buffered solution of 35 mmol/L [44]. This has potential implications for children on cyclic PD where the short
dwell times would predispose to constant exposure of the peritoneal membrane to an acidic pH.
The creation of the multichamber bag allowed
introduction of bicarbonate-based solutions with
bicarbonate at high pH separated from glucose
and electrolytes in an acid milieu, resulting in
lower creation of GDPs during sterilization, a
neutral pH after mixing, and at least 24-hour stability. Two solutions were initially commercially
produced, Physioneal™, a bicarb (25  mmol/L)/
lactate (15 mmol/L) solution, and Bicavera™, a
pure bicarbonate (34  mmol/L) solution. Both
were shown in adults to achieve acidosis correction. Additionally, pure bicarbonate use was


E. Harvey

associated with increased protein catabolic rates,
lower peritonitis rates, and better preservation of
residual renal function [38].
Single buffer PDS may be associated with
elevated blood pCO2 (bicarbonate-buffered solutions) and peritoneal bicarbonate loss (lactate-­
buffered solutions), whereas mixed buffer
solutions (lactate + bicarbonate) may be more
physiological in their regulation, based on studies
of effluent and plasma acid-base concentrations
in both adults and children [40, 45].
The use of bicarbonate/lactate solutions with a
total buffer of 39–40 mmol/l has been associated
with the development of alkalosis [46], most
notable in Japanese adults due to lower dietary
protein intake [47]. This has prompted the development of solutions with a total buffer of
35 mmol/L (bicarbonate 25 mmol/L and lactate
10 mmol/L) with two different calcium concentrations (1.25 mmol/L and 1.75 mmol/L) which
have been shown to reduce alkalosis and correct
acidosis while maintaining similar creatinine
removal and UF [47].
Balance™  Balance™ (Fresenius Medical Care) is
a neutral pH, lactate-based solution with low GDPs,
produced in a two-chamber bag. The specific composition is outlined in Table  14.1. The balANZ
study conducted in Australia and New Zealand was
a randomized trial of 185 incident adult PD patients
with residual renal function comparing Balance™
to cPDS over a 2-year period. Significant outcomes
from primary and secondary analyses [30, 48, 49]

are summarized as follows: the use of Balance™
was associated with initial lower peritoneal UF at 3
and 6 months, which improved over the study duration; a longer time to anuria; reduced peritonitis
rates and severity; increased peritoneal transport at
1 month which remained stable compared to a progressive increase with cPDS; and comparable technique survival. Increased solute transport over time
correlated with GDP exposure and not glucose
exposure.
Pediatric Experience  In children on APD,
Bicavera™ has been shown to improve acidosis
correction compared to lactate-based cPDS.  It
was also associated with higher peritoneal cancer