Effect of peritoneal dialysis fluid composition on peritoneal area available for exchange in children
Michel Fischbach1,
Joëlle Terzic1,
Sylvie Chauvé2,
Vincent Laugel1,
Audrey Muller3 and
Börje Haraldsson4
1Nephrology Dialysis Transplantation Children's Unit, Strasbourg, 2Baxter SAS, Maurepas, 3Pharmacological University, Strasbourg, France and 4Department of Nephrology, Göteborg University, Sahlgrenska University Hospital, Gothenburg, Sweden
Correspondence and offprint requests to: Professor Michel Fischbach, Nephrology Dialysis Transplantation Children's Unit, Hôpital de Hautepierre, Avenue Molière, 67098 Strasbourg, France. Email: Michel.Fischbach{at}chru-strasbourg.fr
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Abstract
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Background. Although conventional peritoneal dialysis fluids (PDFs), such as Dianeal®, are non-physiological in composition, new PDFs including Physioneal® have a more neutral pH, are at least partially buffered with bicarbonate and, most importantly, contain low concentrations of glucose degradation products (GDPs).
Methods. To evaluate the impact of new PDFs in childcare, we performed a comparative crossover study with Dianeal® and Physioneal®. We examined both intraperitoneal pressure (IPP), which partly reflects pain induction, and the total pore area available for exchange, which indicates the number of capillaries perfused in the peritoneal membrane at any given moment and therefore partly reflects peritoneal dialysis capacity. The IPP was determined after inflow of 1000 ml/m2 body surface area (BSA) of dialysate (intraperitoneal volume; IPV). The steady-state unrestricted area over diffusion distance (A0/
x, in cm2/cm per 1.73 m2 BSA) was calculated from the three-pore theory. Six children were enrolled in the study. On the first day, two consecutive peritoneal equilibration tests of 90 min each were performed using first Dianeal® and then Physioneal®. On the second study day, the procedure was repeated with the fluids given in the opposite order.
Results. The mean IPP normalized to IPV (ml/m2) was significantly higher for Dianeal® (9.5 ± 0.9 cm/1000 ml/m2) than for Physioneal® (7.9 ± 1.2 cm/1000 ml/m2, P < 0.01). The mean A0/
x was 17 ± 4% larger with Dianeal® (36 095 ± 2009 cm2/cm per 1.73 m2) than with Physioneal® (31 780 ± 2185 cm2/cm per 1.73 m2, P < 0.001; based on 24 data pairs).
Conclusions. These pilot study results suggest a higher biocompatibility for Physioneal® than for Dianeal®. Less inflow pain associated with Physioneal® induced a lower IPP reflecting enhanced fill volume tolerance, and the lower A0/
x reflected less capillary recruitment. Taken together, these results suggest that the new more biocompatible PDFs will improve peritoneal dialysis therapy, although this conclusion will require verification in extended clinical trials.
Keywords: capillary recruitment; children; intraperitoneal pressure; peritoneal dialysis fluid
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Introduction
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Conventional lactate-buffered peritoneal dialysis fluids (PDFs) such as Dianeal®, are non-physiological in composition. In contrast, the new PDFs, including Physioneal®, have low concentrations of glucose degradation products (GDPs) with a more neutral pH and are, at least in part, bicarbonate buffered. These new fluids seem to reduce infusion pain [1,2], have fewer vasodilatory effects [3] and are more biocompatible, resulting in improved membrane and cellular function [4,5].
The quality control of PDFs is about the same as for intravenous fluids. However, the usage of these fluids differs considerably. PDFs are applied locally to the peritoneal surface of the abdominal cavity and are often present 24 h per day, 365 days per year. For adults, annual PD volumes are close to 3000 l or more for each patient. In contrast, intravenous fluids are diluted and buffered directly in the blood compartment and the fluids are given in smaller quantities than PDFs. Moreover, years of PD treatment cause morphological and functional changes in the peritoneal membrane. Thus, after 5 years on PD,
3040% of adult patients appear to develop ultrafiltration failure, which requires transfer of the patients to haemodialysis. It is therefore not surprising that much interest over the last decade has been focused on improving the quality of PDFs. In particular, there has been concern over the presence of small concentrations of GDPs that may exert detrimental effects on the peritoneum. Therefore, different strategies have been developed to eliminate these substances from the commercially available products, and there are now several new PDFs on the market.
In order to evaluate the clinical impact of these new PDFs in childcare, we performed a comparative study examining Physioneal® and Dianeal® while measuring intraperitoneal pressure [6,7], an objective marker of fill volume tolerance [8] that may be related to inflow pain [1,2], and while determining vascular peritoneal membrane area, a marker of capillary recruitment [9].
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Subjects and methods
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Patients
We studied patients with a mean age of 7 ± 2.8 years (range, 14 months to 14 years) undergoing automated PD. Median duration of dialysis at time of enrolment was 21 ± 13 months (range, 12 months to 4 years). All patients had been free of peritonitis for at least 3 months prior to the study. Renal residual function (RRF) was <4 ml/min per 1.73 m2 body surface area (BSA). The RRF was calculated from the mean of urea and creatinine clearances. The protocol was explained to the children and their parents who then gave oral consent. This informed consent was obtained from all patients.
Study protocol
The children were tested during routine days at the hospital, at least 3 h after their nightly automated dialysis sessions with the filled abdominal cavity. While the children were at rest and in a supine position, the peritoneal fill volume (IPV) was set at 1000 ml/m2 in a randomized crossover design (Figure 1). On the first day, Dianeal® 1.36% was given as PDF followed by a second period using Physioneal® 1.36%. On the second day, the order of the PDFs was switched. The PDF glucose concentration (1.36%) was the same during all of the study periods. The dwell time for each study period was 90 min, allowing two short consecutive peritoneal equilibration tests (PETs) on each study day. The time interval between the two PETs was <10 min. Tolerance was assessed by a conventional pain rating index, including a pain scale graduated from 1 to 10 indicating a range of smile to cry. A second measure of tolerance was intraperitoneal pressure (IPP; cm of water) that was determined according to previously described methods in children [6,7]. In brief, the IPP was measured immediately after filling, i.e. at 5 min dwell times for each consecutively prescribed IPV to evaluate the differential impact of fill volume tolerance between the two PDFs. In addition, the children were asked to scale the degree of pain. At the mid-point between the two consecutive PETs, we took a blood sample from each patient to calculate the average dialysate (D) over plasma (P) concentration ratio for the two consecutive PETs for urea, glucose, creatinine (after correction for the interference of glucose) and phosphate. Initial dialysate samples (Di) for urea, creatinine, phosphate, glucose and proteins were taken from dialysate solute concentrations during drainage of the abdominal cavity. Additional samples were taken at completion of infusion at 13 (Di), 15 (D15), 30 (D30), 60 (D60) and 90 min (D90) of dwell time, allowing the D/P and the D/Do ratios to be calculated. It should be emphasized that this procedure is similar to standard PET but is of short duration and takes specific samples. From each dialysate sample, pH was determined using a blood gas analyser at a standardized temperature of 25°C.

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Fig. 1. The study design. Six children at rest and in a supine position were given a peritoneal fill volume (IPV) of 1000 ml/m2 BSA in a randomized crossover design. On the first day, Dianeal® (Dia) was given first, followed by Physioneal® (Phy). On the second day, the opposite order was used. For more details, see Subjects and methods. Only one blood sample (B) per study day was performed in the time interval between the two consecutive PETs; this interval lasted <10 min.
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Calculations
Intraperitoneal pressure (IPP). Measurements of IPP (in cm of water) were normalized to the intraperitoneal volume (IPV), and were thus expressed as cm per 1000 ml/m2 to allow for inter-individual comparisons. In the same way, IPP was normalized to body mass index (BMI), determined as kg body weight/m2.
Mass transfer area coefficient (MTAC) and the APEX time. Efficiency of dialysis was determined from the dialysate to plasma ratios (D/P) for each tested solute at the different dwell times. The plasma water concentrations were calculated as P/0.93. The APEX time [10] was determined from the time point of intersection of the D/P urea curve and the D/D0 glucose curve (Appendix 1).
The mass transfer area coefficient (MTAC, in ml/min per 1.73m2) was calculated using the Henderson method [11], with the following equation:
 | (1) |
where D(t) is the dialysate concentration of the solute (urea, creatinine and phosphate) at time t of the dwell time, P is the concentration of the solute in plasma water, and VAV is the weighted average of the peritoneal volume of the dwell inlet, outlet and residual volumes [11]. The residual volume was estimated using Twardowski's standard equation [11] from the average of the creatinine and urea residual volumes. The difference between the inlet and the oulet volumes was assumed to reflect the ultrafiltration volume.
Total pore area available for exchange over diffusion distance (A0/
x). The total pore area over diffusion distance (A0/
x, in cm2/cm/1.73 m2) was calculated using a three-pore model [9,12] The equations used are described in Appendix 2.
Statistical analyses
Results are presented as means ± SEM. A t-test paired design was used to analyse the effects of the two PDFs, Dianeal® and Physioneal®. Differences were considered statistically significant at P < 0.05.
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Results
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Intraperitoneal pressure (IPP)
The mean IPP was significantly higher for Dianeal® (9.5 ± 0.9 cm/1000 ml/m2) than for Physioneal® (7.9 ± 1.2 cm/1000 ml/m2, P < 0.01). The same difference was observed if IPP was normalized to BMI for Dianeal® (0.49 ± 0.04 cm/kg/m2) and for Physioneal® (0.42 ± 0.03 cm/kg/m2, P < 0.01) based on 24 data pairs. There was no clinical report of pain during the study, making it impossible to correlate IPP with the conventional pain rating index for children.
Intraperitoneal pH
Although intraperitoneal pH was substantially lower with Dianeal® during the first 15 min of dialysatemembrane contact, this difference rapidly disappeared during the following 90 min observation period (Figure 2; Table 4).

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Fig. 2. The intraperitoneal pH kinetics for Dianeal® and Physioneal® in children (n = 6). The results are means ± SD based on 12 determinations (two in each patient).
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Dialysate over plasma concentration ratios (D/P)
Table 1 shows the D/P concentration ratios for urea, creatinine and phosphate, as well as mean D/Do glucose and mean dialysate protein concentrations (g/l) at each sample time over the PETs for Dianeal® and for Physioneal®, based on a mean of 12 data points per value. There were no differences in ultrafiltration volumes during PETs for the two PDFs.
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Table 1. The average dialysate over plasma (D/P) concentration ratios for urea, creatinine and phosphate, normalized dialysate glucose concentration (D/D0) and dialysate protein concentrations as a function of peritoneal dialysis dwell time using peritoneal dialysis fluids Dianeal® and Physioneal® in children (n = 6)
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MTAC and the APEX time
Table 2 shows mean MTACs (ml/min per 1.73 m2) for urea, creatinine and phosphate at each sample time over the PETs for the two PDFs. The MTACs were significantly larger for Dianeal® than for Physioneal®. These differences occurred during the entire 90 min dwell period and were significant for the urea, creatinine and phosphate solutes. Moreover, the protein concentrations in the dialysate at the end of the dwell time were significantly higher for Dianeal® (0.51 ± 0.03 g/l) than for Physioneal® (0.44 ± 0.04 g/l, P < 0.05).
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Table 2. Average mass transfer area coefficients (MTACs) in ml/min/1.73 m2 for urea, creatinine and phosphate using Dianeal® or Physioneal® during different dwell times in children (n = 6)
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Figure 3 shows that the Apex time was shorter for Dianeal® (55 ± 7.5 min) than for Physioneal® (63 ± 8.4 min, P < 0.01).

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Fig. 3. Apex time for Dianeal® and Physioneal® in children (n = 6), based on average dialysate over plasma (D/P) concentration ratios for urea and normalized dialysate glucose concentration (D/D0). Results are means ± SD based on 12 determinations (two in each patient).
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Total pore area available for exchange over diffusion distance, A0/
x
Table 3 shows steady-state A0/
x (cm2/cm/1.73 m2) for the two PDFs tested at the different times of the PET. The area parameter was significantly larger for Dianeal® than for Physioneal® from 15 to 90 min during the dwell period, and showed a significant peak at 30 min. The mean A0/
x was 17 ± 4% larger with Dianeal® than with Physioneal® (P < 0.001; based on 24 individual data pairs).
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Table 3. Average total pore area available for exchange (A0/ x in cm2/cm/1.73 m2) using Dianeal® or Physioneal® during the different dwell times in children (n = 6)
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Discussion
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The peritoneal membrane acts as a living biological dialysis surface with dynamic properties and complex reaction patterns. Unfortunately, this complexity is aggravated by the presence of different types of peritoneal areas and the lack of discrimination between these types by many research groups. For example, there is the (i) PD fluid contact area, or the wetted membrane, which in humans appears to represent 3060% of the (ii) total anatomical area of the peritoneum [13]. Finally, there is the (iii) peritoneal exchange area (A0/
x) that governs the transperitoneal passage of fluid and solutes. Naturally, the A0/
x is related to the former two types of peritoneal area, but is mainly dependent on the peritoneal microvascular circulation. Thus, the peritoneal fluid contact area is affected by patient posture [9] and by the amount of fill volume [9,14]. As more wetted membrane is recruited, the peritoneal exchange area will increase to result in elevated transport rates between blood and the abdominal cavity. In contrast, the effect of different compositions of intraperitoneal therapeutic solutions on peritoneal transport [3,5,15] is probably not due to alterations in the peritoneal fluid contact area but rather to changes in the exchange area itself. The exchange area, in turn, is the microvascular total pore area which is affected by the number and radii of the functional pores in each capillary. These values, however, appear to be rather constant. More importantly, A0/
x is affected by capillary recruitment since only one out of 510 capillaries normally is perfused at any given time. The composition of the PDFs [3] may affect peritoneal transport by altering the degree of capillary recruitment.
In clinical studies, the new PDFs have been shown to have fewer vasodilatory effects [3] and to cause less infusion pain [1,2]. We therefore conducted the present crossover study in children to compare the effects of Physioneal® and Dianeal®. Dianeal® is a conventional lactate-buffered dialysis fluid that has a low pH and contains GPDs. Conversely, Physioneal® has partial bicarbonate buffering with a neutral pH and a low concentration of GPDs. Because IPV is related to IPP, we measured IPP as a marker of clinical tolerance [1,2,6,16]. We found that infusion of Physioneal®, a new more physiological PDF, induced a lower IPP (7.9 ± 1.2 cm/1000 ml/m2) than Dianeal® (9.5 ± 0.9 cm/1000 ml/m2), a conventional PDF. The lower IPP with Physioneal® may be due to reduced abdominal muscle tension that is secondary to reduced inflow pain [1,2]. Nevertheless, despite the difference in IPP, the children did not have different subjective perceptions of the fill volume of the two PDFs and the perceptions did not correlate with IPP level [17]. In addition, the pH values of the two PDFs were different at the initial period of the dwell (Figure 1) and pH appears to be the main factor associated with inflow pain [1,2]. Nevertheless, intraperitoneal pH was very different between the two PDFs only until 15 min of dwell time (Figure 2). The short duration of acidic pH differs from other data [6] and this may be related to difficulties in pH assessment or temperature standardization in our study. Moreover, the lower IPP with Physioneal® may impact both fill volume prescription by creating better clinical tolerance during cases where enhanced fill volume is necessary, and PD ultrafiltration by enhancing capacity [7,16].
The use of more physiological PDFs may influence peritoneal membrane and cellular function [35,18,19]. The present study with children supported this by showing mean MTACs (ml/min per 1.73 m2) for urea, creatinine and phosphate that were significantly higher for Dianeal® than for Physioneal®, and these differences persisted during the entire 90 min dwell period. In previous studies, there was only a tendency for 1% lower clearances for phosphate and for creatinine when using an additional PDF having neutral pH with bicarbonate buffering and virtually no GPDs [5]. In our study, we used the same glucose concentration (1.36%) in the two PDFs. In contrast, in the study by Schmitt et al. [5], mixed glucose concentrations were used to tailor adequate ultrafiltration for the status for each patient [5,18] and the fluids were studied on two separate days. Instead, the present study protocol allowed for comparisons of different fluids on the same day and there was no day to day variability. These differences are likely to explain the disparities between the present study and that of Schmitt et al. [5]. In our study, the different exchange capacities of the two PDFs were illustrated by the APEX time (Figure 3). The longer APEX time [1,7,10] for Physioneal® than for Dianeal®, combined with lower IPP [16] with Physioneal®, may positively impact the optimization of the ultrafiltration capacity [6,7,16,20]. Nevertheless, there was no difference in ultrafiltrate volume between the two PDFs during the PET. This lack of difference may be due, in part, to the low ultrafiltration achieved using 1.36% PDFs. The longer APEX time for Physioneal® than for Dianeal® should also limit the frequently noted discrepancy between urea and creatinine purification parameters during peritoneal hyperpermeability (or, more accurately, high transporters) that is observed with short APEX times [6,7,10].
We applied the three-pore model to compare the two PDFs for dynamic changes in the vascular peritoneal membrane. The total pore area available for exchange over diffusion distance, A0/
x, was significantly larger for Dianeal® than for Physioneal® from 15 to 90 min of the dwell period, and showed a peak at 30 min (Table 3). This peak increase in A0/
x confirms previous findings obtained using a similar approach [5,9], and is in keeping with previous clinical studies [2,6]. Peak increases in A0/
x were noted for both Dianeal® and Physioneal®, suggesting that neither dialysate acidity, buffer composition (lactate vs bicarbonate) nor GPDs per se were directly involved in this initial peritoneal hyperperfusion [3,5], and indicating that other factors may be involved in this process [5]. The increases in A0/
x were 17 ± 4% greater with Dianeal® than with Physioneal® (see Table 3). This larger total pore area available for exchange with Dianeal® compared with Physioneal® supports a vasoactive role for GPDs [3]. Our results are in agreement with others [3] by showing a capillary recruitment of
20% using conventional acidic pH and lactate-buffered PDF. Thus, the new PDF that induces fewer vasoactive effects may better preserve peritoneal vascular integrity and thereby reduce the rate of vascular sclerosis. The higher protein concentration at the end of the dwell period with Dianeal® compared with Physioneal® suggests that the conventional, standard solution caused a more inflammatory environment, as has been described previously [4].
In summary, our study in children showed that a new more physiological PDF (Physioneal®) and a conventional PDF (Dianeal®) both induced a transient increase in peritoneal surface area during the first 30 min of the dwell period, and that this was independent of pH, presence of lactate and of GPDs. We additionally found that the microvascular three-pore area parameter (A0/
x) available for exchange was 17 ± 4% larger with Dianeal® than with Physioneal®. Thirdly, the APEX time was shorter for Dianeal® than for Physioneal®. Fourthly, the MTACs for urea, creatinine and phosphate were all higher for Dianeal® than for Physioneal®. These APEX and MTAC effects were secondary to the changes in A0/
x. Fifthly, Physioneal® treatment produced a lower IPP (7.9 ± 1.2 cm/1000 ml) than did Dianeal® (9.5 ± 0.9 cm/1000 ml). Taken together, these findings appear to reflect a higher biocompatibility for Physioneal® than for Dianeal® [3,18]. Thus, less inflow pain with Physioneal® may result in lower IPP, and fewer long-term vasoactive effects may reduce the PD exchange rates and may alter the peritoneal membrane morphology. Furthermore, the superior clinical tolerance with Physioneal® may allow further optimization, characterized by increases in IPV. However, our findings obtained from a single day of Physioneal® treatment should be re-evaluated in longer duration clinical trials. They nevertheless indicate that Physioneal® may improve PD therapy for children with chronic renal insufficiency.
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Appendix 1: APEX time
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From the PET equilibration curves, the point at which the over time glucose dialysate desaturation and urea dialysate saturation curves cross can be determined and is called the APEX time point. This point is used in dialysis paediatric care for prescription of PDFs [21] as an index of optimal ultrafiltration time in the case of ambulatory PD prescription. A short APEX time may be related to a hyperpermeable peritoneal membrane state, whereas a long APEX time may be secondary to a hypopermeable state [22].
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Appendix 2: total pore area available for exchange over diffusion distance, A0/ x
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The fundamental significance of the area parameter (A0/
x) is evident from the following equation:
 | (1) |
where MTACX is the mass transfer area coefficient for a solute X, DX is the free diffusion constant and (Ap/A0)X is the pore restriction factor for the solute. DX and (Ap/A0)X are computed from the StokesEinstein radius of the solute [9,12]. Thus, once A0/
x is known, the diffusive transport can be calculated for any solute of known size, allowing for predictions of the net transport of the solute in question.
Initially during a PD dwell, the high concentrations of glucose and lactate, low pH and other factors seem to elicit vasodilatation and recruitment of capillaries. Because this was recognized previously, PDC software was developed and an empirical equation was derived [12] to calculate the steady-state A0/
x:
 | (2) |
where A0/
x(t) is the area parameter at a given time calculated from the steady-state A0/
x. Note that the A0/
x(t) is close to the steady-state value within 30 min, despite an initial 100% increase.
So far, the analysis has focused on diffusive transport and has not involved any specific three-pore model parameter. During PD, there are, however, convective fluxes through the pore pathways. Thus, at any given time (t), the fluid flux through each pore will equal:
 | (3) |
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 pathway.
P(t) and 
prot(t) are the hydrostatic and colloid osmotic pressure gradients at time t, and these values are almost constant. The reflection coefficient for proteins,
y, prot, will determine how effective the colloid osmotic pressure is across that particular pore [12]. The third term in the brackets, 
y,i · 
i(t), is the sum of all effective crystalloid osmotic gradients. For aquaporins, all
s are close to unity, while they are close to zero for the large pores. Finally, the clearances for a solute (ClX) through the small and the large pores are calculated from the individual pore MTAC, Jv and
s using the following non-linear flux equation:
 | (4) |
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:
 | (5) |
More details on the equations used in the modified three-pore model and the properties of the solutes are described elsewhere [12]. Phosphate is of a particular interest, not only from a clinical point of view, but also in terms of modelling. Approximately 30% of plasma phosphate is bound to proteins. Furthermore, phosphate is a buffer with a pK of 6.8, implying that 80% is present in the form of HPO42 and the rest as H2PO4- at physiological pH. The two phosphate ions have similar diffusion constants (1.16 x 10-5/cm2/s), and hence similar StokesEinstein radii (0.28 nm). The pH of the PDF was not corrected since the intraperitoneal pH rapidly approaches physiological levels. However, for shorter dwell times, such as during high volume ambulatory PD, the buffering effect of phosphate may in fact affect its net transport.
In order to use the PET values as data input for the three-pore analysis, we developed new computer software in a previous paper [9]. The effects of dialysis were simulated during the first 60 min with 1 min increments. The parameters of the three-pore model are given in Table 5. A0/
x was allowed to change while the other parameters were assumed to remain constant. In the model, the hydraulic conductance changed in proportion to A0/
x. In each patient, five solutes were used to compute A0/
x, including urea, creatinine, phosphate, protein and glucose. The best fit between measured and modelled D/P and D/D0 concentration ratios was obtained by numerical integration using the values shown in Table 5 as start values in the iterative process.
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Acknowledgments
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This study was supported by Swedish Medical Research Council grants (9898 and 13016) and by Sahlgrenska University Hospital (LUA S11733). Part of this work was presented in abstract form at the 23rd Annual Dialysis Conference, Seattle, March 2003.
Conflict of interest statement. None declared.
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Received for publication: 10. 4.03
Accepted in revised form: 4. 7.03