Peritoneal Dialysis International, Vol.18, pp /98 $ TRANSPORT KINETICS IN CHILDREN

Peritoneal Dialysis International, Vol.18, pp 590-597 0896-8608/98 $300 + 00 Printed in Canada All rights reserved Copyright 1998 International Society for Peritoneal Dialysis INFLUENCE OF AGE, TIME, AND PERITONITIS ON PERITONEAL TRANSPORT KINETICS IN CHILDREN Tuula M. Hölttä, Kai A.R. Rönnholm, Christer Holmberg Pediatric Nephrology and Transplantation, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.Objective:To evaluate peritoneal transport kinetics and its changes over time in children with and without peritonitis, and to record possible differences between children under and over 5.0 years of age..design: A prospective study. The patients underwent a 4- hour peritoneal equilibration test (PET) comprising 2.27% dextrose with a dialysate fill volume of 1000 ml/m2 of body surface area (BSA), at baseline and after a mean of 0.8 :I: 0.4 years of uninterrupted dialysis..patients: We investigated 28 patients on maintenance peritoneal dialysis at baseline; 10 were under 5.0 years of age. The final PET was performed in 21 patients..main Outcome Measures: Peritoneal equilibration rates for urea (U), creatinine (C), glucose (G), sodium, potassium, phosphate, and albumin (A) were measured. Initial and final peritoneal equilibration rates were compared. Mass transfer area coefficients (MTAC) were calculated for urea, creatinine, glucose, and albumin. Residual dialysate volume was determined..results: Median age at first PET was 7.6 years (range 0.3-16.6 yr). The mean (±1 SD) 4-hour dialysate-toplasma (DIP) ratios for U, C, and A were 0.92:1: 0.05,0.70 ± 0.12, and 0.014 :I: 0.007, respectively. The mean 4-hour DIDo ratio for G was 0.32 :I: 0.10. DIP and DIDo results were similar in the two age groups, and peritoneal membrane function remained stable over the study period. Mean MTAC (:1:1 SD) values were: U, 22.3 :I: 4.8; C, 10.9 :I: 4.1; G, 11.1 :I: 3.3; and A, 0.07 :I: 0.03. MTAC data were similar in the two age groups and no significant changes occurred during the study period..conclusions: When the volume tested in children is proportional to BSA, the solute DIP ratios seem to be ageindependent. Our data provide evidence that in pediatric patients MTAC is also age-independent. KEY WORDS: Children; peritoneal equilibration; kinetics; mass transfer area coefficient; MTAC. T he peritoneal equilibration test (PET) has been developed to evaluate baseline peritoneal solute transport rates, and to determine an individual's op Correspondence to: T.M. Hölttä, Hospital for Children and Adolescents, University of Helsinki, Stenbäckinkatu 11, FIN 00290 Helsinki, Finland. Received 5 June 1998; accepted 9 September 1998. timal peritoneal dialysis (PD) regimen. Twardowski et al. (1) classified the test for adult use. The PET has also been used in pediatric patients, but its application has been controversial and problematic. During recent years consensus has been reached that PET should be performed with a volume calculated according to body surface area (BSA), since this is proportional to the surface area of the peritoneal membrane (2). Previous studies demonstrated a trend toward more rapid glucose absorption in small children (35). However, in these studies the test volume was related to body weight. One could argue that this difference is an artefact induced by the smaller fluid volume compared with the peritoneal membrane surface area, leading to more rapid peritoneal equilibration because of the relatively smaller intraperitoneal volume in smaller children. This phenomenon was documented in two recent studies (6,7) made with different test volumes scaled to BSA. Only a few studies have attempted to investigate whether there are differences in peritoneal equilibration between children of various ages when intraperitoneal volumes are related to BSA. Thus, it is still unclear whether peritoneal equilibration is age-related or not. In 1994 Sliman et al. (8) demonstrated an inverse correlation between peritoneal equilibration and age. In 1996 Waradyet al. (9) showed that equilibration was similar in different age groups. The ageindependence of peritoneal equilibration was confirmed by de Boer et al. (10) in 1997; they found fluid kinetics to be independent of age in children over 3 years of age. Little data on the impact of peritonitis on membrane permeability are available in pediatric patients. Also, the possible changes in membrane permeability with time are unknown. The mass transfer area coefficient (MTAC), which characterizes the diffusive permeability of the peritoneal membrane, has been evaluated in only a few pediatric studies. Although MTAC is thought to be dialysate volume independent (2), Keshaviah et al., in an adult study, demonstrated MTAC to increase with increasing dialysate volume (11). However, the

volume independence was demonstrated by Warady et al. for intraperitoneal volumes of 900 and 1100 ml/m2 in pediatric patients (6). In the same study, age-related differences in MTAC were found (9). In another pediatric study, Geary et al. found that MTAC values per kilogram body weight were inversely correlated to age, and did not approach adult values until later childhood (12). However, the test volume used by Geary et al. was low (approximately 30 ml/kg) and correlated to body weight instead of BSA, which makes comparison with adult values difficult. Knowledge of the stability of MTAC from exchange to exchange is still lacking. We have previously reported our experience with PD in children under 5 years of age (13). To characterize peritoneal membrane function, and find possible age and time-related differences in peritoneal transport kinetics, we began to include regular PETs in our dialysis program in 1995. Here we report our experience with PET performed regularly in 28 children on maintenance PD between April 1995 and December 1997. PATIENTS AND METHODS Twenty-eight patients (18 boys, 10 girls) on maintenance PD were studied. The results in children under 5.0 years of age were compared with those in older children. The initial and final PET results were also compared to record any changes in peritoneal membrane function with treatment time and after episodes of peritonitis. The median age at the time of the first PET was 7.6 years (range 0.3 16.6 yr); 10 patients were under 5.0 years of age (1.7 ± 1.3 yr); and 18 were over 5.0 years old (11.2 ± 3.8 yr). Twenty-five were on continuous cyclic peritoneal dialysis (CCPD) and 3 were on tidal peritoneal dialy sis (TPD) at the time of their first PET. Mean dialysis time prior to the first PET was 0.4 ± 0.4 years (range 0.02 1.5 yr). Underlying renal diseases were congenital nephrotic syndrome of the Finnish type (CNF) in 10, cystic kidney disease and obstructive uropathy in 3 patients each, prunebelly and Wegener's granulomatosis in 2 patients each, and Denys Drash syndrome, Alport's syndrome, rapidly progressive glomerulonephritis, IgA nephropathy, lupus erythematosus disseminatus, reflux nephropathy, dysplasia fibromuscularis arterialis, and optic nerve coloboma with renal disease in 1 patient each. Two of the patients (both over 5.0 years) were in cluded twice. In 1, the underlying renal disease was Wegener's granulomatosis; he was without PD for 1 year after kidney transplantation. The other had CNF; she was without PD for 4 months for the same reason. We checked that the inclusion of these patients twice did not skew the data. The PET was always performed at least 1 month after completing antibiotic therapy for peritonitis. Peritonitis therapy in patients treated outside our institution consisted of a loading dose of vancomycin (15 mg/kg) and netilmycin (1.8 mg/kg) intraperitone ally for 2 hours, followed by approximately 8-12 daily exchanges of dialysate containing 30 mg/l vancomycin and 8 mg/l netilmycin. Patients treated at our institution received intermittent intraperitoneal antibiotic treatment: vancomycin in a dose of30 mg/kg in one 6-hour exchange 2 times every 5 7 days, and netilmycin 20 mg/l using once-daily dosing. Antibiotics were later adjusted according to the microbial findings and continued for 8 10 days. Some (53%) of the peritonitis episodes were treated using intermittent therapy and the rest continuously. The final PET was defined as the last PET before kidney transplantation or the last performed before the end of December 1997 in those children who were still on PD. It was performed in mean 2.9 ± 0.2 months (n = 3),5. 7 ± 1.0 mth (n = 5),9.0 ± 0.7 mth (n = 6), 11.6 ± 0.9 mt h (n = 3), 15.2 mth (n = 1), and 19.0 ± 1.1 mth (n = 3) after initial PET, respectively. A 4-hour PET was performed with 1000 ml/m2 BSA of a PD solution containing 2.27% dextrose (Dianeal 2.27%, Baxter Healthcare, Castlebar, Ire land) after an 8-hour dwell with PD solution of the same amount and concentration. During the infu sion the patients were in the supine position, turning from side to side. Immediately after completion of the infusion, 10% of the volume was drained and mixed well, and a 5-mL sample was taken. Other samples were taken after 60, 120, and 240 minutes dwell. The patients were ambulatory during the test. Mter 4 hours the total volume was drained. Ultra filtration (UF) was corrected for the total volume of samples taken during the study. A blood sample was obtained after 120 minutes dwell. The concentrations of glucose, urea, creatinine, sodium, potassium, albumin, and phosphate were determined in dialysate and blood. To achieve a physiologically consistent relationship between the blood and dialysate concentrations of the particular solute, all serum values, except albumin, were expressed as concentrations per unit volume of plasma water. This was achieved by dividing the serum values, except that of albumin, by a factor of 0.93, thereby correcting the plasma volume for protein and lipid contents (14). Sodium and potassium were measured by flame photometry in serum and with a direct ion-selective electrode in the dialysate, albumin in serum by the bromcresol purple reaction and immunoturbidometrically in the dialysate. Both blood and dialysate urea were measured by the urease method, creatinine by the kinetic Jaffe method, and phosphate by photometry. Blood glucose was measured using a

glucose oxidase electrode and enzymatically in the dialysate. Because a high glucose concentration in PD solutions interferes with the creatinine assay used, a correction factor was determined with the help of creatinine-free glucose solutions. Dialysate creatinine was computed as corrected creatinine (μmol/l) = creatinine (μmol/l) -0.51 x dialysate glucose (mmol/l). Total body water was estimated from height and body weight, using the child-specific equation offriis Hansen (15). Body surface area was calculated using the childspecific equation of Haycock et al. (16). Peritoneal transport was estimated from the dialysate-toplasma ratios (DIP) of urea, corrected creatinine, sodium, potassium, albumin, and phosphate calculated at 0, 1,2, and 4 hours. Similarly, the transport of glucose across the peritoneum was used to estimate the ratio of dialysate glucose at a given time to the dialysate glucose level at time 0 (D/Do). Determination ofmtac was based on the two-pool Pyle-Popovich model (17), and was calculated as a weighted average: where t is time, Co is dialysate solute concentration at time 0; CD is the dialysate solute concentration at time t in minutes; CB is the average solute blood concentration at time t; Vo is the volume infused plus the pre-exchange residual volume; and V D is the geometric average ofvo and volume drained plus the preexchange residual volume. The sampling times used for MTAC calculation were 120 and 240 minutes, because of the computer model we used. Thus, the weights used for computing the weighted average of the MTAC were the squares of the sampling times at 120 and 240 minutes. All data are expressed as medians or means ± 1 SD. Statistical comparisons of normally distributed values were performed using the t-test, of distributionfree values for two independent groups using the Mann Whitney U test, and for one-sample paired readings using the Wilcoxon signed rank test. Associations between variables were evaluated by quadratic regression analysis. Any p values less than 0.05 were considered significant. RESULTS The mean test volume in the initial PET in 28 patients was 984 ± 29 ml/m2 (967 ± 31 ml/m2 in children under, and 994 ± 23 ml/m2 in children over 5.0 years of age). The mean pre-exchange residual volume was 153 ± 68 ml/m2 (181 ± 76 ml/m2 and 137 ± 59 ml/m2 for children under and over 5.0 years of age, respectively). The mean 4-hour UF was 180 ± 99 ml/m2 (173 ± 124 ml/m2 and 184 ± 86 ml/m2, respectively). Seven children had a history ofperitonitis 2.8 ± 1.6 (range 1.2 4.9) months prior to initial PET and 21 were peritonitis -free. No significant difference in equilibration was found between these two groups. Thus, all initial PETs were pooled to construct the equilibration curves. The pooled solute equilibra tion curves for urea, creatinine, phosphate, and glucose are illustrated in Figure 1. The absolute numbers for the initial PETs in children under and over 5.0 years of age are given in Table 1. No significant difference was found between these two age groups. A final PET was performed in 21 children at a mean of 0.8 ± 0.4 (range 0.2 1.7) years after the first PET (1.3 ± 0.8 years after initiation ofpd). The mean test volume in the final PET was 1005 ± 20 ml/m2 [1009 ± 56 ml/m2 in children under (n = 9), and 1002 ± 13 ml/m2 in children over 5.0 years of age (n = 12)]. The final mean pre-exchange residual volume was 186 ± 58 ml/m2 (201 ± 39 ml/m2 and 179 ± 68 ml/m2 for children under and over 5.0 years of age, respectively). The final mean 4-hour UF volume was 160 ± 129 ml/m2 (144 ± 157 ml/m2 and 173 ± 109 ml/m2, respectively). When the initial and final PET results were compared, slight increases were found in the DIP and D/Do ratios (Figure 2) and a decrease in the 4-hour UF, but these differences were not significant at any time point. To further investigate any longitudinal changes in peritoneal membrane function, the patients were divided into 2 groups: group 1, those with no history of peritonitis during the study period; and group 2, those with a history of at least one episode of peritonitis during the study period, irrespective of whether they had had a peritonitis more than 1 month prior to their initial PET. The incidence of peritonitis was: one episode in 3 patients, two episodes in 3 patients, and three episodes in 2 patients. The causal organisms isolated were: Staphylacaccus aureus in 7 episodes, Enterabacter in 3 episodes, Pseudamanas aeruginasa in 2 episodes (in 1 patient), and Enteracaccus, Streptacaccus viridans, and Acinetabacter calcaaceticus in 1 episode each. In the peritonitis group, the final PET was performed 4.7 ± 3.7 (range 1.1 12.5) months after peritonitis. The mean interval between PETs was 0.72 ± 0.39 years in group 1 (n = 13) and 0.89 ± 0.50 years in group 2 (n = 8). The changes in the equilibration rates of creatinine in 4 hours for both groups are illustrated in Figure 3. The equilibration decreased in the peritonitis group only in the patient with two Pseudamanas episodes (pointed out in Figure 3, upper). There were no significant changes in the equilibration rates of creatinine or phosphate in either group with time, or in any other equilibration rates studied (data not shown).

Peritoneal transport kinetics in patients with CNF (10 of28 patients, 8 under 5.0 years ofage) were compared with those in other patients. Children with CNF showed a slightly higher membrane permeability for albumin in their initial PET (the mean 4-hour D/P ratio for albumin was 0.016 ± 0.006 in the CNF patients, and 0.013 ± 0.008 in the non-cnf patients). This difference in the 4-hour D/P ratio for albumin was not seen in the final PET. The children with CNF also tended to equilibrate other solutes faster in the initial PET, but this difference was reduced or had disappeared in the final PET compared with the noncnf patients. Thus, the difference in equilibration between CNF and non-cnf patients was significant only for the initial4- hour D/Do ratio of glucose (0.26 ± 0.06 and 0.35 ± 0.10, p = 0.027), and D/P ratio ofphosphate (0.65 ± 0.12 and 0.53 ± 0.11, p = 0.013). The MTAC data for urea, creatinine, glucose, and albumin are given in Table 2. There was no difference in MTAC between the children under and over 5.0 years of age, nor was there any correlation between MTAC and age in quadratic regression analy

SiB. When all results were pooled, no significant difference was found between the initial and final MTAC, or between subgroups of children with and without a history of peritonitis during the entire study period, although the children with a history of peritonitis tended to have a higher MTAC. The children with CNF tended to have higher initial and lower final MTACs than the other children, but these differences were not significant. This finding is compatible with the higher D/P at the initial PET compared to the final PET in the patients with CNF, as described above. DISCUSSION Our results, using an intraperitoneal volume re lated to BSA, support the age-independence of peritoneal transport kinetics in children. We found neither a significant difference in D/P ratio between the children under and over 5.0 years of age, nor a corre

lation between D/P and age. Although the children with CNF tended to equilibrate faster in their initial PET, the difference in D/P ratio between the patients with and those without CNF was significant only for 4-hour glucose and phosphate in the initial PET. Peritonitis 4 weeks before PET did not affect the D/P ratio. When the results of initial and final PETs were compared, peritoneal membrane function remained stable over at least 6 months. No correlation was found between MTAC and age. In our study, the 4-hour solute D/P data for glucose and sodium were similar to the Pediatric Peritoneal Dialysis Study Consortium (PPDSC) data using an intraperitoneal volume of 1100 ml/m2 ofbsa (9). Our 4-hour D/P ratio for sodium and DIDo for glucose were equal to those in the PPDSC study, but the 4-hour D/P ratio for creatinine was 6% higher, and for urea and potassium 10% higher. A possible expla nation for our slightly higher values could be the smaller test volume and the large number of children with congenital nephrosis (36%). An alternative explanation, suggesting that peritoneal equilibration decreases with time, could be the much shorter mean dialysis time prior to the initial PET in our patients; only 0.4 years compared with 2 years in the PPDSC study. Schaeferet al. (18) studied 20 pediatric patients, using the same intraperitoneal volume as we did, but without correcting plasma volume for protein and lipid content. If we recalculate our data without correction of serum values, our 4-hour D/P ratio for potassium is 9% higher and for phosphate 16% lower, while the other values remain much the same. Very few studies have measured alterations in peritoneal equilibration rate over time in pediatric patients. Nishi et al. (19) found that peritonitis was a risk factor for deterioration of peritoneal function. In 6 children aged 11 ± 8 years with a history of peritonitis, he found a significant decrease in the D/P creatinine ratio at 4-hour dwell time in the final PET compared with the initial PET (the mean interval between the PETs was 28 ± 12 months). In 6 children of similar age without peritonitis, the final4-hour D/P creatinine ratio was unchanged (the mean interval between PETs was 22 ± 12 months). However, the DIDo

glucose ratio at 4-hour dwell time was unchanged over time in both groups. Several adult studies, however, have failed to show changes in membrane transport after episodes of peritonitis. In an adult study, Davies et at. (20) suggest that solute transfer increases and UF decreases with time after only 6 months on PD treatment, the increase being accelerated by peritonitis. Peritonitis, especially when caused by Pseudamanas, is reported to cause reduction of peritoneal membrane function (21,22). In our study, peritoneal membrane function remained stable even after episodes of peritonitis. We had only 1 patient with Pseudamanas peritonitis and her membrane perme ability decreased. Membrane permeability in the initial PET was slightly higher in children with CNF compared to other children, but this difference disappeared in the final PET. The mean test volume was not lower in CNF patients compared to other patients, and dialysis time prior to the initial PET was similar. CNF patients have low serum albumin, prealbumin, and protein levels, and muscular hypotonia. They also have cholesterol, lipoprotein, and phospholipid abnormalities. Pre albumin normalizes after 1 month on PD. Albumin, protein, cholesterol, and lipoprotein levels do improve within 3 months, but will not reach normal values (23). In addition, children with CNF, in contrast to other predialysis patients, are not uremic. They become uremic after nephrectomy. These metabolic differences may have an impact on membrane permeability, especially during the first months on PD. Our MTAC values for urea were higher than in the PPDSC study (22.3 ± 4.8 ml/min and 18.4 ± 4.0 ml/min), and slightly lower for glucose (11.1 ± 3.3 ml/min and 12.9 ± 5.0 ml/min). The MTAC for creatinine was similar (10.9 ± 4.1 ml/min and 10.7 ± 3.7 ml/min). In the PPDSC study, more dialysate samples were taken into account for the calculations (0, 30, 60, 120, 180, and 240 minutes) compared with the 120 and 240-minute samples used by us. This makes their calculation more accurate, but probably the most important explanation of the higher MTAC for urea in our patients is the higher membrane transport rate. The PPDSC study showed significant agedependence for MTAC of glucose, whereas we failed to show any age-dependence for MTAC ofurea, creatinine, glucose, or albumin. In our study, the MTACs also remained stable over time, as did equilibration, and no differences were found in the MTACs between the groups with and without peritonitis. Our study confirms age-independence for the equilibration rates and MTACs in children when the test volume is related to BSA. Peritoneal membrane function remained stable over at least 6 months of PD therapy. In the beginning, children with CNF showed a trend toward higher peritoneal membrane permeability. 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