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Abstract. The most important of the parameters that describe volume was raised from 800 to 1400 ml/m2 BSA, the steady-
exchange across the peritoneal membrane is the total pore area state A0/⌬x increased significantly by 21%, i.e., from 19,900
over diffusion distance (A0/⌬x). It determines the rate of ⫾ 1200 to 24,000 ⫾ 1450 cm2/cm per 1.73 m2 (n ⫽ 8). A
diffusion and mainly seems to reflect the number of capillaries further increase to 2000 ml/m2 did not result in any change of
available for exchange. In the present study, a simplified three- A0/⌬x. Moreover, steady-state A0/⌬x fell significantly when
pore analysis was used to estimate A0/⌬x from peritoneal the patients were standing, 21,900 ⫾ 1400 compared with
equilibration tests. Two groups of children (mean age, 9.5 yr) 29,400 ⫾ 1330 cm2/cm per 1.73m2 (n ⫽ 6) obtained in the
who were on chronic peritoneal dialysis underwent studies supine position. There was a transient (⬍30 min) increase in
with peritoneal equilibration tests. In the first group of chil- A0/⌬x initially during the dwell, probably reflecting vasodila-
dren, three levels of fill volumes were used in each patient. In tion and recruitment of capillaries. It is concluded that factors
the second group of patients, the effects of posture and dwell such as the intraperitoneal fill volume, posture, and dwell time
time were analyzed from four consecutive peritoneal dialysis all dynamically affect the total pore area available for
samples obtained after 15, 30, 60, and 90 min. As the fill exchange.
Peritoneal dialysis (PD) has become an increasingly popular Three basic PDC parameters characterize the peritoneal
therapy modality, particularly for children. There are many membrane. First and most important is the “area parameter,” or
differences between hemodialysis and PD, one being that the the total pore area over diffusion distance (A0/⌬x), which is a
latter uses a biologic membrane instead of an artificial dialyzer. fundamental physiologic expression. A0/⌬x determines the
Therefore, it is even more important to measure and individ- mass transfer area coefficient (MTAC) for any hydrophilic
ualize the dose of dialysis during PD (1). In the past decade, solute. Note that A0/⌬x is not unique for the three-pore model
our knowledge of the transport processes across the peritoneal but rather is a fundamental physicochemical parameter for
membrane has expanded considerably. In particular, the three- transport across porous membranes. Second, the “absorption”
pore model has been most successful in predicting the trans- parameter (JvAR) denotes the final reabsorption rate of fluid
peritoneal exchange of fluid and solutes. According to this from the abdominal cavity to blood when the glucose gradient
theoretical model introduced by Rippe et al. (2,3), the perito- has dissipated. This lumped parameter includes lymph flow (L)
neal membrane contains three populations of functional pores: and the “Starling forces” across the capillary wall, i.e. JvAR ⫽
the water-exclusive aquaporins (1, 3, and 4) (4), the small-pore LpS 䡠 [⌬P-⌬] ⫹ L, where ⌬P and ⌬ are the net hydrostatic
pathways (radius, 4.7 nm), and the large-pore pathways (radi- and colloid osmotic pressure gradients, respectively, and is
us, 25 nm). The frequencies of the pores are inversely related the average reflection coefficient for proteins. Third, the “plas-
to their pore sizes. Thus, there are approximately 106 aquapor- ma loss” parameter (JvL) equals the flow of plasma-like fluid
ins and 104 small pores on every large pore. With the three- from blood to the abdominal cavity through the large pores.
pore model, it is possible to predict the exchange of solutes The reflection coefficient for proteins across the large pores,
depending on their molecular size and the osmotic effect of L, is close to 0, so JvL ⬇ LpS 䡠 fL 䡠 ⌬P (see reference 7 for
various substances (5). Indeed, the model seems to be universal details).
for microvascular beds in general (6). These physiologic con- The complete analysis of the three-pore parameters requires
cepts also have been used to estimate the PD capacities (PDC) a rigorous measuring protocol that includes information of dwell
of individual patients (7).
times, intraperitoneal volumes, and concentrations of various sol-
utes from several PD exchanges. However, the fundamental area
parameter, A0/⌬x, can be estimated from the dialysate over
Received June 21, 1999. Accepted November 30, 2000. plasma concentration ratios (D/P) derived from individual perito-
Correspondence to Dr. Börje Haraldsson, Department of Nephrology, Sahl-
neal equilibration tests (PET). This is made possible by assuming
grenska University Hospital, SE-413 45 Gothenburg, Sweden. Phone: ⫹46-31-
34-21701; Fax: ⫹46-31-41-23-32; E-mail: borje.haraldsson@kidney.med.gu.se the other three-pore parameters to be constant. Hereby, we apply
1046-6673/1207-1524
the complete three-pore analysis to the PET data, allowing for
Journal of the American Society of Nephrology both diffusive and convective transport of solutes through the
Copyright © 2001 by the American Society of Nephrology small- and large-pore pathways.
J Am Soc Nephrol 12: 1524 –1529, 2001 Effects of Fill Volume and Posture on A0/⌬x 1525
In a previous study (8), the effects of posture were evaluated MTACX is the mass transfer area coefficient for a solute X. DX is
in terms of PET (9) and intraperitoneal pressures. Both param- the free diffusion constant, and (Ap/A0)X is the pore restriction factor
eters were affected by posture as well as by fill volume (FV) for the solute. Moreover, DX and (Ap/A0)X are computed easily from
(10). Many investigators interpret changes in PET in terms of the Stokes-Einstein radius of the solute (see reference 7). Thus, once
A0/⌬x is known, the diffusive transport can be calculated for any
“transport” or “peritoneal permeability” (8,11). Albeit useful
solute of known size, thus allowing for predictions of the actual net
from a practical point of view, these terms do not, however, transport of the solute.
give us any information of the underlying mechanisms in the Initially during a PD dwell, there seems to be a vasodilation and
peritoneal membrane. PET and A0/⌬x from PDC have been recruitment of capillaries (13). This was recognized early in the PDC
compared against an independent technique, namely the uptake software (7), and an empirical equation was derived previously (14) to
of iohexol from the abdominal cavity (12). The results showed calculate the steady-state A0/⌬x:
that A0/⌬x was superior to PET in predicting the plasma
A0 A0
appearance of iohexol. Hence, A0/⌬x gives a better description (t) ⫽ 䡠 共1 ⫹ e⫺0.08䡠t兲 (2)
of the peritoneal function than PET (12). Indeed, several fac- ⌬x ⌬x
tors may affect the D/P ratios and, hence, PET: (1) the area Where A0/⌬x(t) is the area parameter at a given time calculated from
available for exchange (A0/⌬x), (2) the intraperitoneal volume, the steady-state A0/⌬x. According to equation 2, already after 30 min
(3) the rate of “ultrafiltration,” (4) the lymph flow, (5) the pore A0/⌬x(t) is close to the steady-state value (⫹9%), despite an initial
sizes, and (6) the relative number of pores. 100% increase.
In the present study, we used a simplified three-pore analysis So far, the analysis has focused on diffusive transport and has not
(7) to estimate the area parameter, A0/⌬x, from PET data from involved any specific three-pore model parameter. During PD, how-
children who were on PD. We studied the dynamic effects on ever, there are convective fluxes through the pore pathways. Thus, at
A0/⌬x of using different FV and different body positions and any given time t, the fluid flux through each pore will equal:
the influence of dwell time. Our results show that such anal-
yses give valuable insights into the peritoneal function of
Jvy ⫽ LpS 䡠 fy 䡠 关⌬P(t) ⫺ y,prot 䡠 ⌬prot(t) ⫺ 冘
y,i 䡠 ⌬i(t)兴 (3)
individual patients. where LpS is the ultrafiltration coefficient and fy is the fraction of LpS
accounted for by the particular pore pathway y. Thus, f is close to 1%
for the aquaporins, 5% for the large pores, and 94% for the small-pore
Materials and Methods pathway. ⌬P(t) and ⌬prot(t) are the hydrostatic and colloid osmotic
Study Groups pressure gradients at time t, values that are almost constant. The
Experiments were performed on two groups of patients. In group reflection coefficient for proteins, y, prot, will determine how effec-
A, the effect of FV was studied in eight children with a mean age of tive the colloid osmotic pressure is across that particular pore (7). The
9 yr and 6 mo (range, 2 to 16 yr). In group B, we studied six children third term in the brackets, ⌺y, i⌬(t), is the sum of all effective
with a mean age of 9 yr and 5 mo (range, 5 to 16 yr) in supine and crystalloid osmotic gradients. For aquaporins, all are close to unity,
upright positions. Part of the patient material has been published whereas they are close to 0 for the large pores. Finally, the clearances
previously (8), but the data were completely reanalyzed. for a solute (ClX) through the small and the large pores are calculated
for from the individual pore MTAC, Jv and , using the following
Variables nonlinear flu equation (7):
冉 冊冋 册
The concentrations of urea, creatinine (after due correction for the
D
interference of glucose), phosphate, protein, and glucose were ana- Jv(t) 䡠 1 ⫺ X 1 ⫺ (t) 䡠 e⫺Pe(t)
lyzed in plasma (P) and dialysate (D). D/P concentration ratios for the P
ClX(t) ⫽ ⫺Pe(t) (4)
solutes were computed, except for glucose, where the initial concen- 1⫺e
tration (D0) was calculated and D/D0 values were estimated.
where D/P is the dialysate over plasma concentration ratio at time t
and Pe(t) is the Peclet number at time t, which is given by the
Study Protocol following equation:
Effect of Fill Volume. Three levels of peritoneal FV were used:
800, 1400, and 2000 ml/m2. The dialysate concentrations were ana- Jv(t) 䡠 共1 ⫺ X兲
Pe(t) ⫽ (5)
lyzed after 60 min in a supine position. MTACX
Effect of Posture. The effect of posture was estimated by mea-
suring the D/P and D/D0 values after 60 min in a supine or standing More details of the equations used in the modified three-pore
position. The FV was 1000 ml/m2 in this group of patients. model and the properties of the solutes are described elsewhere
Effect of Time. The three-pore model analysis was performed on (6,7,14). Phosphate is of a particular interest, not only from a clinical
four consecutive PD samples obtained after dwell times of 15, 30, 60, point of view but also in terms of modeling. Approximately 30% of
and 90 min with FV of 1000 ml/m2 on the same patients as in B. plasma phosphate is bound to proteins. Furthermore, phosphate is a
buffer with a pK of 6.8, suggesting that 80% is present in the form of
HPO42⫺ and the rest as H2PO4⫺ at physiologic pH. The two phos-
Calculations phate ions have a similar diffusion constant (1.16 10⫺5 cm2 s⫺1),
The fundamental significance of the area parameter (A0/⌬x) is hence Stokes-Einstein radii (0.28 nm). No correction seems to be
evident from the following equation: required for the pH of the PD fluid, because the intraperitoneal pH
冉冊
rapidly will approach the physiologic levels. However, for shorter
Ap A0
MTACX ⫽ DX 䡠 䡠 (1) dwell times, such as during high-volume ambulatory PD, the buffer-
A0 X
⌬x ing effect of phosphate may affect transport.
1526 Journal of the American Society of Nephrology J Am Soc Nephrol 12: 1524 –1529, 2001
To use the PET values as data input for the three-pore analysis, we
developed new computer software. The effects of dialysis were sim-
ulated during the first 60 min with 1-min increments. The parameters
of the three-pore model are given in Table 1. Only A0/⌬x was allowed
to change; the other parameters were constant. The hydraulic conduc-
tance changed in proportion to A0/⌬x. In each patient, five solutes
were used to compute A0/⌬x, namely urea, creatinine, phosphate,
protein, and glucose. The best fit between measured and modeled D/P
and D/D0 concentration ratios were obtained by numeric integration
using the values in Table 1 as start values in the iterative process.
Statistical Analyses
Results are given as mean ⫾ SEM. A t-test paired design was used
to analyze the effects of posture and FV. P ⬍ 0.05 was considered to
be statistically significant.
Figure 1. The steady-state total pore area over diffusion distance
Results (A0/⌬x) plotted against the intraperitoneal fill volumes (FV) in eight
Only changes of A0/⌬x predicted the biologic data. Thus, children who were on peritoneal dialysis (PD). Note the significant
changing any of the other parameters (the final reabsorption increase in A0/⌬x as FV is raised from 800 to 1400 ml/m2.
rate, the large pore fluid flux, the small- and/or the large-pore
radius, the hydrostatic pressure gradients, the number of aqua- cm) of the individual patients were plotted against the actual
porins, or the ultrafiltration coefficient) resulted in less preci- FV (in ml; Figure 2).
sion in the predictions of the D/P concentration ratios. In These estimates of A0/⌬x were based on three-pore analysis
addition, none of these parameters was able to describe the of the 60-min D/P concentration ratios for urea, creatinine,
effects of FV and/or position. Therefore, this article focuses on phosphate, and protein as well as the D/D0 concentration ratio
the changes of A0/⌬x. for glucose. To visualize the reliability of these calculations,
we used the computed A0/⌬x value to simulate D/P and D/D0
Effects of Peritoneal FV ratios for the five solutes. As shown in Figure 3, the modeled
The steady-state total pore area over diffusion distance, D/P or D/D0 values were in close agreement with the measured
A0/⌬x, was 19,900 ⫾ 1200 cm2cm⫺1(1.73 m2 body surface data. Thus, the linear regression of Figure 3 is y ⫽ 0.94x ⫹
area)⫺1 for a FV of 800 ml/m2 (789 ⫾ 22 ml/m2). For an FV 0.014, r2 ⫽ 0.974. As previously mentioned, except for A0/⌬x,
of 1400 ml/m2 (1360 ⫾ 22 ml/m2), the A0/⌬x was 24,000 ⫾ none of the parameters in Table 1 was able to describe the
1450 cm2/cm per 1.73m2. The 21% increase was highly sig- effects of changing FV. We used equation 2 in these calcula-
nificant (P ⬍ 0.001; n ⫽ 8). Increasing the FV further to 2000 tions to estimate the steady-state A0/⌬x but similar results with
ml/m2 (1950 ⫾ 33 ml/m2) did not induce any significant the non–steady state A0/⌬x.
change of A0/⌬x being 24,500 ⫾ 1700 cm2/cm per 1.73m2.
Figure 1 illustrates the results. Effects of Posture
To ensure that the relationship in Figure 1 was not caused by In the supine position the steady-state total pore area over
the normalization procedure, the uncorrected A0/⌬x (in cm2/ diffusion distance, A0/⌬x, was 29,400 ⫾ 1330 cm2 /cm per
strated that the area parameter (A0/⌬x) in the upright position 4. Akiba T, Ota T, Fushimi K, Tamura H, Hata T, Sasaki S,
was 74% of that estimated when the patient was lying down. Marumo F: Water channel AQP1, 3, and 4 in the human perito-
The MTAC for small solutes initially are higher during a PD neum and peritoneal dialysate. Adv Perit Dial 13: 3– 6, 1997
dwell and decrease gradually within the first hour. In a recent 5. Rippe B, Stelin G, Haraldsson B: Computer simulations of
study on rats, this was found to be due to vasodilation rather peritoneal fluid transport in CAPD. Kidney Int 40: 315–325,
than interstitial discharge (13). Such effects are encountered in 1991
the present three-pore model by the empirical equation (equa- 6. Rippe B, Haraldsson B: Transport of macromolecules across
microvascular walls: The two-pore theory. Physiol Rev 74: 163–
tion 2) (7), giving steady-state A0/⌬x.
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The present three-pore analysis is based on D/P (and D/D0)
7. Haraldsson B: Assessing the individual Peritoneal Dialysis Ca-
concentration ratios for several solutes. The analysis was sim-
pacities of individual patients. A clinical tool based on the
plified, however, by assuming the other PDC parameters (7) of
three-pore model. Kidney Int 47: 1187–1198, 1995
Table 1 to be constant. This assumption was necessary because 8. Fischbach M, Terzic J, Dangelser C, Schneider P, Roger ML,
a more complete determination of the three-pore parameters Geisert J: Effect of posture on intraperitoneal pressure and peri-
would require more laborious collection of data, i.e., the PDC toneal permeability in children. Pediatr Nephrol 12: 311–314,
protocol (7). However, the errors with respect to the absolute 1998
values for A0/⌬x were found to be small, as was evident after 9. Twardowski ZJ: Clinical value of standardized equilibration tests
selective alteration of the other parameters in Table 1. For in CAPD patients. Blood Purif 7: 95–108, 1989
example, altering the ultrafiltration coefficient with a factor of 10. Fischbach M, Terzic J, Dangelser C, Schneider P, Roger ML,
2 affects A0/⌬x less than 1%. The solutes measured represent Geisert J: Improved dialysis dose by optimizing intraperitoneal
small solutes, and the discriminative power for detecting volume prescription thanks to intraperitoneal pressure measure-
changes of the pore radii therefore is somewhat limited. How- ments in children. Adv Perit Dial 13: 271–273, 1997
ever, changes in the pore radii or the relative number of pores 11. Imholz AL, Koomen GC, Voorn WJ, Struijk DG, Arisz L,
did not result in acceptable simulations of the biologic data, Krediet RT: Day-to-day variability of fluid and solute transport
whereas changes in A0/⌬x did. in upright and recumbent positions during CAPD. Nephrol Dial
In conclusion, the most important physiologic parameter that Transplant 13: 146 –153, 1998
controls peritoneal exchange, A0/⌬x, can be estimated ade- 12. Johnsson E, Johansson A-C, Andréasson B-I, Haraldsson B:
quately from PET data. There was a good fit between the D/P Unrestricted pore area (A0/⌬x) is a better indicator of peritoneal
ratios estimated from children and those calculated by the function than PET. Kidney Int 58: 1773–1779, 2000
three-pore model in its present form. The three-pore analysis is 13. Carlsson O, Rippe B: Enhanced peritoneal diffusion capacity of
a theory based on our current understanding of capillary phys- 51Cr-EDTA during the initial phase of peritoneal dialysis dwells:
Role of vasodilatation, dialysate ‘stirring’, and of interstitial
iology that may facilitate our understanding of the clinical
factors. Blood Purif 16: 162–170, 1998
situations during PD. Thus, the “area” (A0/⌬x) increases with
14. Haraldsson B, Broms E, Johansson AC: How to evaluate and
FV and when the patient goes from standing to a supine
optimize peritoneal dialysis treatment. Nephrol Dial Transplant
position. The results underscore the dynamic nature of the area
13[Suppl 6]: 112–116, 1998
available for peritoneal exchange. Finally, an FV of approxi- 15. Renkin EM: Control of microcirculation and blood-tissue ex-
mately 1400 ml/m2 seems to be optimal to ensure maximum change. In: Handbook of Physiology, Vol. 4, Microcirculation,
recruitment of peritoneal capillaries in children. edited by Renkin EM, Michel CC, Bethesda, MD, American
Physiological Society, 1984, pp 627– 687
Acknowledgments 16. Chagnac A, Herskovitz P, Weinstein T, Elyashiv S, Hirsh J,
This study was supported by the Swedish Medical Research Coun- Hammel I, Gafter U: The peritoneal membrane in peritoneal
cil (grants 9898 and 13016), the Knut and Alice Wallenberg Research
dialysis patients: Estimation of its functional surface area by
Foundation, and Sahlgrenska University hospital (LUA B313 03).
applying stereologic methods to computerized tomography
scans. J Am Soc Nephrol 10: 342–346, 1999
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