Standard Peritoneal Permeability Analysis in Children
ANTONIA H. M. BOUTS*,
JEAN-CLAUDE DAVIN*,
JAAP W. GROOTHOFF*,
SJOERD PLOOS VAN AMSTEL*,
MACHTELD M. ZWEERS and
RAYMOND T. KREDIET
*Emma Children's Hospital Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands. Department of Nephrology, Academic Medical Center, University of
Amsterdam, Amsterdam, The Netherlands.
Correspondence to Dr. Antonia H. M. Bouts, Emma Children Hospital, G8-205,
Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Phone: +31 20 5662727; Fax: +31 20 6917735; E-mail:
a.h.bouts{at}amc.uva.nl
Abstract. Peritoneal transport characteristics in children on
peritonealdialysis (PD) has been reported to be different compared toadults.
However, various test methods can influence this difference.Thirty-one
standard peritoneal permeability analyses (SPA) wereperformed in 18 PD
children with a median (range) age of 9.8yr (2 to 19) and a median duration
of PD of 2.6 yr (0.19 to6.8). The median mass transfer area coefficient
(MTAC) for creatininewas 9.6 ml/min per 1.73 m2 (4.4 to 18.0), and
for urea 17.3ml/min per 1.73 m2 (12.2 to 22.8). The median
dialysate to plasmacreatinine ratio (D/PCr) was 0.69
(0.44 to 0.92), the glucoseabsorption 59% (23 to 75), and the
D/D0 for glucose 0.38 (0.23to 0.62). The median clearance
of ß2-microglobulin was923 µl/min per 1.73 m2
(366 to 1828), of albumin 103 µl/minper 1.73 m2 (55 to 211), of
IgG 48 µl/min per 1.73 m2(20 to 105), and of
2-macroglobulin 12 µl/min per 1.73m2 (5 to
49). No correlation was found between these resultsand age or PD time. The
restriction coefficient for macromoleculesindeed increased with duration of
PD treatment (r = 0.38, P= 0.03). The median transcapillary
ultrafiltration rate was1.2 ml/min per 1.73 m2 (-0.01 to 2.8), the
net ultrafiltrationrate 0.2 ml/min per 1.73 m2 (-1.97 to 1.82),
and the effectivelymphatic absorption rate 1.04 ml/min per 1.73 m2
(-0.06 to2.91). When corrected for body surface area, no differenceswere
found in peritoneal fluid and solute transport characteristicsbetween
children and adults. No effect of time on PD on thetransport parameters was
found in a cross-sectional analysis,except for an increase of the restriction
coefficient to macromolecules.This finding is similar to observations in
adults. Therefore,the present study showed no evidence for the common belief
thatthe peritoneal membrane in children is different from that inadult
patients.
The assessment of peritoneal transport characteristics in childrentreated
with chronic peritoneal dialysis (PD) is mostly doneby the peritoneal
equilibration test (PET), developed by Twardowskiet al.
(1). Through standardization of
this test, adult patientscould be categorized into low, low-average,
high-average, andhigh transporters according to their peritoneal solute
transportresults (2). More
recently, the standard peritoneal permeabilityanalysis (SPA) has been
described by our group in adult patients
(3).In this modification and
extension of the PET, the transportof low molecular weight solutes is
expressed as mass transferarea coefficients (MTAC) instead of dialysate to
plasma (D/P)ratios. Furthermore, peritoneal fluid kinetics during
the dwellare determined using intraperitoneally administered dextran70, and
the peritoneal clearances of various serum proteinsare calculated. These are
used to compute the restriction coefficient(RC), which represents the
intrinsic permeability of the peritonealmembrane. It appeared that MTAC had a
better discriminativepower than D/P ratios, especially in the
extreme ranges (3).
Furthermore,the MTAC was not influenced by the tonicity of the dialysis
fluids(4), and also not by the
dialysate volume, e.g., 2 or 3 L
(5).Possible differences in
peritoneal transport between childrenand adults have been discussed by many
authors. Some authorsdescribed higher D/P ratios of small solutes
during a PET inchildren than adults
(6,7,8)
and also higher D/P ratios in youngerinfants than in older children
(6,7).
However, others were notable to confirm this
(9,10).
These conflicting results are likelyto be caused by differences in
standardization of the instilledvolume, either per kilogram body weight or
per square meterbody surface area
(11). The results of MTAC
measurements inchildren have not been reported frequently. Warady et
al. foundhigher MTAC in younger infants compared to older children
(9),but Geary et al.
described the opposite (12).
The aim of thepresent study was to establish normal values of the SPA in
children,to compare MTAC of low molecular weight solutes with D/P
ratios,and to compare the results obtained in children with those inadult PD
patients.
Thirty-one SPA were performed in 18 children on PD. Their ageranged from 2
to 19 yr with a median of 9.8 yr. The median lengthof duration of PD
treatment was 2.6 yr (range, 0.2 to 6.8).SPA were done routinely, every year,
on a voluntary basis. Thefirst SPA was performed 2 to 6 mo after the
initiation of dialysis.In one patient, an extra test was done because of
electrolytedisturbances. In 9 children, only one SPA was performed, in6 two,
in 2 three and in 1 four tests (Table
1). None of thepatients had peritonitis on the day of the test or
in the 4preceeding weeks. The mean peritonitis incidence, defined asnumber
of episodes per patient year, was 0.8
(Table 1). Theresults of 138
SPA performed in 86 adult patients with a medianage of 51 yr (range, 21 to 80
yr) and a median duration of PDtreatment of 2.1 yr (range, 0.33 to 13.5 yr)
were used to comparewith those in children.
Table 1. Duration of PD at first SPA, patient age at subsequent SPA, and
peritonitis incidence in all 18 individual patientsa
The SPA consisted of a 4-h dwell of glucose 1.36% dialysis solution
(Dianeal®;Baxter BV, Utrecht, The Netherlands) to which a volume marker,
dextran70, 1 g/L (Macrodex; NPBI, Emmercompascuum, The Netherlands)was
added. The mean test volume was 1170 ml/m2 (range, 910 to1500).
This corresponds with 42 ml/kg (range, 30 to 56). Beforeinstillation of the
test solution, the peritoneal cavity wasrinsed with glucose 1.36% dialysis
solution, of which the volumewas equal to the volume of the test bag. Samples
of the dialysate(10 ml) were taken from the test bag before inflow and after
drainage,and from the peritoneal cavity 10, 20, 30, 60, and 180 min after
instillation.To avoid a dead space effect, 100 to 200 ml was temporarily
drainedbefore the test sample was taken. At the end of the test, the
peritonealcavity was rinsed again with a 1.36% glucose solution for
measurementof the residual volume (RV). Blood samples were taken at time0
and after 240 min. To prevent possible anaphylaxis to dextran,Dextran 1
(Promiten®; NPBI), 20 ml was given intravenouslyafter the first blood
sample was taken (13).
Measurements
Creatinine, urea, and urate concentrations in dialysate andplasma were
measured by enzymatic methods (Boehringer Mannheim,Mannheim, Germany). For
glucose, a glucose oxidase-peroxidasemethod was used, and determined on an
autoanalyzer (SMA andSMA-II; Technicon Corp., Terryton, NJ). Total dextran
was measuredby HPLC (14).
ß2-microglobulin was determined by a microparticleenzyme
immunoassay (Abbott Laboratories, Abbott Park, IL). Albumin,IgG, and
2-macroglobulin were measured by nephelometry (BN100;
Behring,Marburg, Germany).
Calculations Solute Transport. The peritoneal transport rates of low molecular
weightsolutes (creatinine, urea, and urate) were expressed as bothMTAC and
as D/P ratios. The MTAC was calculated according tothe Waniewski
model (15) with the following
equation:
This model corrects for convective transport by a factor F =0.5.
P is the plasma concentration corrected for plasma water.
V10and V240 represent the
intraperitoneal volume, and D10 and
D240the dialysate concentration at t = 10 and
t = 240 min, respectively.Vm is the mean
intraperitoneal volume, calculated as the areaunder the intraperitoneal
volume versus the time curve, dividedby the dwell time. This area
was calculated by the trapeziumrule
(16). Glucose transport was
expressed as the Dt/Do ratioor the
percentage glucose absorption. The glucose absorptionwas calculated as the
difference between the amount of glucoseinstilled and the amount recovered,
relative to the amount instilled.
The protein clearances (ß2-microglobulin, albumin, IgG,and
2-macroglobulin) were calculated as follows:
In this equation, Pr240 and PrRV
means the protein content inthe drained bag and the residual volume,
respectively. The Prpis the plasma protein concentration
and t is the dwell time.The intrinsic peritoneal permeability to
macromolecules wasassessed by the peritoneal restriction coefficient
(RC)
(4,17,18).
Thisis the exponent of the power relationship between the peritoneal
clearances(C) of proteins and their free diffusion coefficients in
water(Dw).
in which a is a constant.
Fluid Kinetics. Transcapillary ultrafiltration rate (TCUFR),
effectivelymphatic absorption rate (ELAR), and net ultrafiltration rate
(NUFR)were calculated as described previously
(4). Briefly, the ELARcan be
calculated as the dextran disappearance rate in whichall pathways of uptake
into the lymphatic system, both subdiaphragmaticand interstitial, are
included
(19,20):
In this equation, Dxi is the dextran concentration in
the instilledfluid, Dxr the recovered dextran mass, and
Dxgeom the geometricmean of the dialysate dextran
concentration. The TCUFR was calculatedfrom the dilution of dextran 70
(21). The NUFR was calculated
asthe difference between the transcapillary ultrafiltration andthe effective
lymphatic absorption divided by the dwell time.The residual volume
(RV) was calculated by the following equation
(22):
in which rs is the rinsing solution, ts is the testsolution, V is
the instilled volume, and C is the dextran concentrationafter
drainage.
The MTAC, the protein clearances, and the fluid kinetic measurementswere
all corrected for body surface area (BSA). The BSA wascalculated according to
Mostellers' formula:
Statistical Analyses
Results are given as mean and median values, SD, and ranges.Differences
between adults and children were tested with theMann-Whitney nonparametric
rank test. Correlations between timeon PD or age and fluid/solute transport
parameters were testedwith the Spearman nonparametric rank test. Correlations
anddifferences between two methods (D/P and MTAC) were tested with
theSpearman rank correlation test and the Bland and Altman method
(23,24).
Forthe latter analysis, all values were expressed as percentagesof their
means.
Solute Transport
Results of low molecular weight solute transport are given in
Table 2.No differences were
found between the MTAC in adults andthose in children except for the
MTACurate, which was lowerin children than in adults. No
significant changes of the MTACCrin relation to age or duration of
PD treatment were found (Figure
1).Furthermore, no relationship between the instilled test volume
eitherper m2 or per kg and MTACCr was present
(Figure 2). The lackof a
relationship between MTAC and age, duration of treatment,and instilled volume
was also found for the other low molecularweight solutes (data not shown).
The D/PCr in adult CAPD patientswas higher compared to
children, but the D240/D0 for glucose
andthe glucose absorption were not different. The D/PCr
and theD240/D0 for glucose in
children had no relationship with ageor duration of PD treatment (data not
shown).
Figure 2. MTACCr in relation to the instilled volume per kg or
m2 (NS).
Comparison of MTAC and D/P or Dt/D0 Ratios
A strong correlation was present between the D/PCrversus theMTACCr and
D240/D0glucversus the percentage glucose absorption
(Figure 3).The mean of the
D/PCr and the MTACCr compared with the
differenceof these two measurements, however, showed no random distribution
ofthe differences between MTAC and D/P ratio, but a significant
relationshipbetween the differences and the means
(Figure 4). This suggeststhat
systematic errors are present according to the magnitudeof the transport
measurements. Only for values between 80 and110% of the mean was the
agreement between the D/P and MTACgood. For glucose, the best
agreement was for values between95 and 105% of the mean. It appears from
Figure 4 that the D/P
ratiogives an overestimation compared to the MTAC in the lower rangeand an
underestimation in the higher range.
Figure 3. Correlations between MTAC and D/P or D/D ratios. (A)
Relation between D/P240 creatinine and MTACCr
(r = 0.92, P < 0.0001). (B) Relation between
D240/D0 glucose and glucose absorption
(r = 0.97, P < 0.0001).
Figure 4. (A) Comparison of D/PCr. (B) Comparison of
D/D0 gluc and glucose absorption, both with the Bland and
Altman method. In this approach, the mean values of D/P and MTAC are
plotted against their differences. In case of optimal agreement between these
two methods, the values are randomly distributed, with a narrow range, around
the mean of difference. [UNK], mean of differences; [UNK]-, 95% confidence
interval.
Transport of Macromolecules
The results of the peritoneal protein clearances are shown in
Table 3.No differences were
found between children and adults exceptfor the albumin clearance, which was
marginally higher in children.No effect of age or duration of PD treatment on
the proteinclearances was found (data not shown). Only the restriction
coefficientincreased significantly with the duration of PD treatment
(Figure 5).
Figure 5. Relation of the restriction coefficient (RC) for macromolecules with
duration of peritoneal dialysis (r = 0.39, P = 0.03).
Fluid Kinetics
The results of the TCUFR, ELAR, NUFR, and RV are shown in
Table 4.No significant
differences were found between children andadults. In children, no relation
was observed between age andfluid transport parameters, nor did time on PD
influence thesefluid transport parameters significantly
(Figure 6).
Figure 6. Relation between age and fluid kinetic parameters: transcapillary
ultrafiltration rate (TCUFR), effective lymphatic absorption rate (ELAR), and
net ultrafiltration rate (NUFR) (NS).
The present study has shown that the results of the standardperitoneal
permeability analysis in children were not essentiallydifferent from results
obtained in adult patients. The few exceptions,i.e., the lower
MTACurate and the marginally higher albuminclearance, were most
likely caused by the relatively large numberof adult patients and/or the
narrow range of values resultingin statistically significant but clinically
not relevant differences.This is illustrated by our finding that a
significant differencefor the albumin clearance was not found when t
test was used.
The MTAC and D/P ratios of low molecular weight solutes are
dependenton the vascular surface area of the peritoneum
(25). In adults,the
peritoneal surface area ranges from 1.0 m2
(26) to 1.3 m2
(27).A newborn has a
peritoneal surface area of 0.11 m2
(26). Esperancaand Collins
have demonstrated that the ratio between peritonealsurface area and body
weight in newborns is about twice thatof the adult
(26). Assuming that an adult
has a BSA of 1.73m2 and a newborn 0.2 m2, the
peritoneal surface area expressedper square meter body surface area is 0.6
m2 both in adultsand infants. The BSA can be approximated by the
weight and isrelatively large in small children. Furthermore, BSA is a more
accuratepredictor of drug dosage in infants and children because the
clearanceof a variety of drugs is greater in children than in adultswhen
expressed in terms of total body weight
(28).
In the past, the PET in children was most often performed witha test
volume in milliliters per kilogram. When expressed persquare meter this gives
a relatively low volume, especiallyin small children, and thus a more rapid
equilibration of solutesresulting in higher D/P ratios
(29,30.
Therefore, it is likelythat when the instilled volume is corrected for BSA,
childrenwill not have enhanced peritoneal transport capacity comparedto
adults, as has been described previously
(31,32,33).
MTACare less influenced by the instilled test volume than D/P ratios
inthe clinically relevant ranges in adult patients
(5). Waradyet al.
described no difference in MTACCr using test volumesof 900 or 1100
ml/m2, but higher D/P ratios for creatinine inthe lower
test volumes (29).
Exceptionally low intraperitonealvolumes may result in low MTAC values
because the peritonealmembrane surface area might not been used completely
(34). Weused a test volume
ranging between 900 and 1500 ml/m2 (30 to55 ml/kg) and could not
find a relation between MTACCr and theinstilled volume.
Relationship between Transport Parameters and Age
No significant changes in D/P ratios and MTAC were found according
toage. Other studies have demonstrated higher D/P ratios in small
infantsthan in older children. This could result from the rapid peritoneal
soluteequilibration observed when a relatively low test volume persquare
meter is used
(6,7,8,9,10).
Furthermore, the age distributionin the children group can influence these
results. In our study,five children were under the age of 5 yr. Warady et
al. comparedD/P and MTAC measurements in children with a test
volume of1100 ml/m2 and found no differences in D/P ratio
for creatinine,urea, and glucose according to age. However, they showed
higherMTAC values (calculated according to the Pyle-Popovich method)for
glucose and creatinine in younger infants than older children.The authors
suggested that this might be the result of maturationalchanges in the
peritoneal membrane or differences in the effectiveperitoneal membrane
surface area (9). Geary et
al. found anincrease of the MTAC (calculated by the Garred formula)
accordingto age but used lower test volumes (32 ± 5 ml/kg)
(12).This could result from
using only a part of the peritoneal surfacearea especially in the young
children. Moreover, these authorsexpressed their MTAC values in ml/min.
Reviewing their datamakes it likely that no significant correlation between
ageand MTAC would have been found with the MTAC expressed in ml/minper 1.73
m2. The differences in test volumes we used did notinfluence the
results between MTAC and age significantly whentested with a partial rank
correlation test (r = 0.33, P = 0.09).The peritoneal
protein clearances, i.e., ß2-microglobulin,albumin,
IgG, and 2-macroglobulin, did not change significantly
accordingto age. Quan and Baum described an inverse correlation betweenBSA
and peritoneal protein loss expressed in mg/m2 per d andsuggested
that the greater amount of protein loss may resultfrom both a higher
permeability and a greater peritoneal surfacearea in children
(35). The protein clearances
we measured reflectthe functional state of the peritoneum and cannot be
extrapolatedto 24-h loss of proteins, because it is dependent on the dwell
timeand the number of bag exchanges. During the first hour of thedwell time,
the protein clearance is higher than the consecutivehours, probably caused by
vasodilation induced by the dialysissolution resulting in an increase in
effective peritoneal surfacearea
(36). However, from our
results, especially the similarvalues for the restriction coefficient to
macromolecules, wecannot conclude that a higher peritoneal permeability in
childrenwould exist. No influence of age on the fluid kinetic parameterswas
found when corrected for BSA. Similar findings have beendescribed by
Reddingius et al.
(37).
Comparison of Children with Adults
We found a lower D/PCr in children than in adults. This
is contradictoryto other studies
(6,7,8,9,10).
This is most likely the resultof a lower average test volume per square meter
used in theadult group, which was 1000 ml/m2
(3). MTAC values were not
differentbetween children and adults. Glucose transport was similar inboth
groups. The peritoneal protein clearances in children andadults were also not
different with the exception of the marginallyhigher albumin clearance. We
did not find changes in peritonealfluid transport parameters between children
and adults whencorrected for BSA in both groups. This is in agreement with
thestudy of Reddingius et al.
(37). The D/P ratios
in childrenoverestimated the MTAC values in the lower ranges and
underestimatedthem in the higher ranges. These results are similar to those
foundin adults (3). This
suggests that a different peritoneal transportcategory can be assigned to the
same patient when using eitherD/P ratio or MTAC.
Relationship between Transport Parameters and Duration of PD
Treatment
The MTAC of the low molecular weight solutes creatinine, glucose,and
urate, as well as the D/P ratios, did not change accordingto time on
PD. The time on PD in our study may have been tooshort for detecting changes
in fluid transport. The median PDtime was 2.6 yr, the maximum 6.7 yr. The
first SPA test wasnot always performed in the first year of treatment, and in
mostcases only two tests per patient were done. Instead of a cross-sectional
analysis,a more extensive longitudinal follow-up will clarify individual
changesaccording to duration of PD treatment. The clearances of thehigh
molecular weight proteins did not change significantlyaccording to duration
of PD treatment. However, an increaseof the restriction coefficient for
macromolecules occurred inrelation to the duration of PD treatment,
indicating an increasedsize selectivity or a reduced peritoneal permeability
for highermolecular weight solutes. This has also been described in adults
(38),but has not been
reported in children.
In summary, the SPA test is a good method to evaluate peritonealtransport
function in children. MTAC is preferred to D/P ratiobecause it is
less influenced by dialysis mechanics since theMTAC is independent from
exchange volumes and the dialysateglucose concentration. SPA results in
children are similar toadults when corrected for BSA in both groups. No
significantchanges in peritoneal fluid and solute transport were found
accordingto the duration of PD treatment with the exception of an increaseof
the restriction coefficient for macromolecules.
Acknowledgments
This study was supported by the Dutch Kidney Foundation (Grant
C95.1464).
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Received for publication April 13, 1999.
Accepted for publication September 7, 1999.
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Abstract
Introduction
2-macroglobulin 12 µl/min per 1.73 m2 (5 to
49). No correlation was found between these results and age or PD time. The
restriction coefficient for macromolecules indeed increased with duration of
PD treatment (r = 0.38, P = 0.03). The median transcapillary
ultrafiltration rate was 1.2 ml/min per 1.73 m2 (-0.01 to 2.8), the
net ultrafiltration rate 0.2 ml/min per 1.73 m2 (-1.97 to 1.82),
and the effective lymphatic absorption rate 1.04 ml/min per 1.73 m2
(-0.06 to 2.91). When corrected for body surface area, no differences were
found in peritoneal fluid and solute transport characteristics between
children and adults. No effect of time on PD on the transport parameters was
found in a cross-sectional analysis, except for an increase of the restriction
coefficient to macromolecules. This finding is similar to observations in
adults. Therefore, the present study showed no evidence for the common belief
that the peritoneal membrane in children is different from that in adult
patients. 
