METHODS

Twenty-six male Sprague-Dawley rats with an average body wt of 290 g (range 280 to 300 g) were divided into four groups. Each rat was anesthetized with a single intraperitoneal injection of 50 mg/kg pure pentobarbital sodium (Pharmacia, Sweden). This anesthesia was reported not to alter the peritoneal transport in rats⁹. The fur over the abdominal wall was clearly shaved. The animal was laid in a supine position and was kept at 37°C with a heating pad (CMN/Microdialysis, Stockholm, Sweden). Isotonic saline, 1 ml/hour, was injected subcutaneously to prevent hypovolemia. A multiholed silastic catheter (Venoflon, 0.8 mm internal diameter; Helsingborg, Sweden) was inserted percutaneously in the left lower quadrant of the abdomen for dialysis fluid infusion and sampling. The experiment was started by giving an intraperitoneal injection of 25 ml (group Con25, N = 6) or 40 ml (group Con40, N = 7) of sterile 1.36% glucose dialysis fluid. In the other two groups, 0.01% sterile hyaluronan (protein and endotoxin free; average molecular wt 500,000; Hyal, Toronto, Canada) was added to 25 ml (group HA25, N = 6) or 40 ml (Group HA40, N = 7) of sterile 1.36% glucose dialysis fluid. This concentration of hyaluronan has been shown to protect the hyaluronan layer around the human peritoneal methothelial cells²⁴ and the peritoneum from injury caused by saline infusion²⁵, as well as to effectively decrease the peritoneal fluid absorption²³. All the fluids were prewarmed to 37°C and mixed with 18.5 kBq ¹³¹I-human serum albumin (RISA; Isopharma AS, Kjeller, Norway). A small dose (0.2 g/liter) of human albumin was added to the solution to minimize adhesion of tagged albumin to the surface of the catheter. The solution was administered via a three-way valve (Viggo, Connecta, Helsingborg, Sweden) and the catheter, over a period of about one minute, and allowed to remain in the peritoneal cavity for four hours. The intraperitoneal hydrostatic pressure was measured after the infusion using a water manometer connected to the peritoneal catheter, setting the reference level at the heart of the rat. Dialysate samples (0.4 ml) were taken at 0, 3, 15, 30, 60, 90, 120, 180 and 240 minutes after the dialysis fluid had been infused. Prior to each sampling, 1 ml of the dialysate was flushed back and forth five times through the catheter. Blood samples were drawn at 0, 120 and 240 minutes from the tail artery. After 240 minutes, the peritoneal cavity was opened and the dialysate was collected using a syringe and preweighted gauze tissue.

Dialysate samples (0.1 ml) and blood samples (0.1 ml of plasma) were analyzed for RISA activity on a Gamma Counter (Packard Instrument Company, Meriden, CT, USA) for 10 minutes each. Dialysate and plasma concentrations of urea (urease-glutamate dehydrogenase method), protein (Coomassie Brilliant Blue dye binding method) and glucose concentration (hexokinase method) were analyzed using a Multistat Autoanalyzer (Instrumentation Laboratory, Spokane, WA, USA).

The intraperitoneal dialysate volume was estimated from the dilution of RISA with corrections made for the elimination of the RISA from the peritoneal cavity. The total peritoneal fluid absorption rate as assessed by RISA elimination coefficient (K_E ml/min) was calculated as described previously^26,27. The intraperitoneal volume change (net ultrafiltration) at time t was calculated as the intraperitoneal volume at time t (V_t) minus the infused volume (V₀). The transcapillary ultrafiltration rate (Q_u) was defined as the rate of intraperitoneal volume change plus the rate of fluid absorption (K_E)²⁷. The direct lymphatic absorption of fluid from peritoneal cavity was assessed as the RISA elimination rate from the peritoneal cavity to the blood (K_EB ml/min). The K_EB was calculated from the rate of increase of RISA amount in plasma divided by the average intraperitoneal RISA concentration⁸. The plasma volume was set at 3.6 ml/100 g body wt⁸. The remaining part of fluid absorption to the peritoneal tissue interstitium and capillaries (K_ET ml/min), was calculated as K_E minus K_EB.

The dialysate-to-plasma-solute concentration ratios (D/P) for all the investigated solutes were calculated by dividing the dialysate concentration of a solute at a certain time with the aqueous concentration of the investigated solute in plasma²⁸. If no blood sample was taken at the same time as a dialysate sample, then the blood concentration of solute was linearly interpolated from the blood sample taken before and after this moment²⁹. The D/D₀ for glucose was calculated as the dialysate glucose concentration (D) divided by the glucose concentration in the fresh dialysis solution (D₀). The clearance of the investigated solutes was calculated as the total amount of the solute in the drained dialysate at 240 minutes minus the infused amount and divided by the mean blood concentration of the solute and the dwell times.

The diffusive mass transport coefficients (K_BD, ml/min) were estimated using the modified Babb-Randerson-Farrell (BRF) model as described previously^30,31. The model describes the net change of the solute amount in peritoneal dialysate over time increment equal to the rate of solute flow between blood and dialysate due to combined diffusion, convective transport, and peritoneal absorption of the solute. In addition, in this study, we set the sieving coefficients (S) for glucose and urea to 0.55 and for total protein to 0.05 based on previous studies^3,32.

Two-way ANOVA with repeated measurements and one-way ANOVA were applied to compare intraperitoneal volume, ultrafiltration rate, K_E, K_EB, K_ET, D/P ratios, and K_BD. When ANOVA showed a significant difference among the four groups, then Scheffe's F-test was used to compare the difference between different groups. Special attention was paid to compare the results between the Con25 group and the Con40 group, between the Con25 and the HA25 groups, and between the Con40 and the HA40 groups using the unpaired Student's t-test. The results are expressed as mean SD. A P value of less than 0.05 was considered significant.

RESULTS

Fluid transport

Fluid transport characteristics are shown in Figures 1 and 2 and Table 1. The increase in dialysate fill volume resulted in a significant increase (P < 0.01) in intraperitoneal hydrostatic pressure (IPP) from 1.7 0.5 cm H₂O in the Con25 group to 5.1 1.0 cm H₂O in the Con40 group Table 1. No significant differences in IPP were found between the Con25 and HA25 groups or between the Con40 and the HA40 groups Table 1. Although the transcapillary ultrafiltration rate (Q_u) between three minutes and 240 minutes of the dwell was higher in the Con40 group (0.024 0.004 ml/min) as compared to the Con25 group (0.017 0.004 ml/min, P < 0.01; Table 1), the net ultrafiltration volume was significantly lower (P < 0.01) in the Con40 group as compared to the Con25 group (Figure 1 and Table 1), which was due to a significantly higher peritoneal fluid absorption rate (as assessed by the RISA elimination rate, K_E; Figure 2 and Table 1).

Figure 1.

Changes in intraperitoneal volume (net ultrafiltration) versus time. Symbols are: () 25 ml control group (Con25, N = 6); () 40 ml control group (Con40, N = 7); () 25 ml with 0.01% hyaluronan group (HA25, N = 6); () 40 ml with 0.01% hyaluronan group (HA40, N = 7). Data are mean SD. Significant differences (P < 0.05) were found between the Con40 and Con25 groups, between the HA25 and Con25 groups and between the HA40 and Con40 groups (Two-way ANOVA for repeated measures).

Full figure and legend (19K)

Figure 2.

The ¹³¹I-human serum albumin (RISA) elimination rate from the peritoneal cavity. Abbreviations are: K_E, total RISA elimination rate representing the fluid absorption rate from the peritoneal cavity; K_EB, RISA elimination rate to the blood from the peritoneal cavity representing the peritoneal lymphatic absorption; K_ET, RISA elimination rate to peritoneal tissue. Symbols are: () 25 ml control group (Con25); () 25 ml with 0.01% hyaluronan group (HA25); , 40 ml control group (Con40); , 40 ml with 0.01% hyaluronan group (HA40). Data are mean SD. Significant differences are marked: **P < 0.01 compared to their respective control groups, that is, between the Con40 and Con25 groups, between the HA25 and Con25 groups and between the HA40 and Con40 groups.

Full figure and legend (51K)

Table 1 - Fluid transport parameters and intraperitoneal hydrostatic pressure among the four groups (mean SD).

Full table (43K)

The K_E values were significantly lower in the two hyaluronan groups as compared to their respective control group, that is between the HA25 group versus the Con25 group (P < 0.05) and between the HA40 group versus the Con40 group (P < 0.01; Table 1 and Figure 2). Therefore, the ultrafiltration volume was significantly higher in the two hyaluronan groups as compared to their respective control groups (Table 1 and Figure 1). There was no significant difference in the direct lymphatic absorption as assessed by K_EB among the four groups (Table 1 and Figure 2), and thus the differences in K_E between the groups were mainly due to the differences in fluid absorption to the adjacent peritoneal tissue as assessed by K_ET Figure 2.

Glucose transport

Although the diffusive mass transport coefficient for glucose did not differ among the four groups Table 2, the D/D₀ of glucose decreased markedly slower in the Con40 group as compared to the Con25 group Figure 3. However, the total absorbed amount of glucose during the dwell was significantly higher with high fill volumes than with low fill volumes Figure 3. The D/D₀ was initially lower and the total absorbed amount of glucose was initially higher (only at 15 min and 30 min of the dwell) in the HA25 group compared to the Con25 group (Figure 3; P < 0.05). After 30 minutes of the dwell, D/D₀ as well as the total absorbed amount of glucose were not significantly different between the two groups. The D/D₀ of glucose also tended to be lower in the HA40 group as compared to the Con 40 group, although no statistical difference was found between the two groups Figure 3.

Figure 3.

Dialysate glucose concentration (D) to fresh dialysate glucose concentration (D₀) ratio (A) and total absorbed amount of glucose (B) versus dwell time. Symbols are: () 25 ml control group (Con25, N = 6); () 40 ml control group (Con40, N = 7); () 25 ml with 0.01% hyaluronan group (HA25, N = 6); () 40 ml with 0.01% hyaluronan group (HA40, N = 7). Significant differences (P < 0.05) were found between the Con40 group and the Con25 group for both D/D₀ and the total absorbed amount of glucose. The D/D₀ was significantly lower and the total absorbed amount of glucose was significantly higher in the HA25 group at 15 and 30 minutes of the dwell compared to the Con25 group.

Full figure and legend (34K)

Table 2 - Diffusive mass transport coefficients, K_BD (ml/min), for glucose, urea, and total protein as well as peritoneal clearances, l/min, for urea and total protein (mean SD).

Full table (29K)

Transport of other solutes

The D/P for urea and protein were significantly lower in the Con40 group as compared to the Con25 group (Figure 4; P < 0.05). There were no significant differences in D/P of urea between the Con25 and the HA25 groups or between the Con40 and the HA40 groups Figure 4. There were no significant differences in K_BD values for urea and for protein between the Con25 and Con40 groups as well as between the two hyaluronan groups and their respective control groups Table 2. The urea clearance was significantly higher in the two high volume groups (Con40 and HA40) as compared to the two low volume groups (Con25 and HA25; Table 2). The addition of hyaluronan resulted in significantly higher urea clearance as compared to their respective control groups Table 2. The dialysate protein concentration was significantly higher during the dwell in the two hyaluronan groups as compared to the control groups of the same volume, resulting in significantly higher (P < 0.05) D/P of protein in the two hyaluronan groups as compared to the respective control groups Figure 4. This was due to a markedly higher protein appearance in the dialysate during the initial three minutes of the dwell. There was no significant difference in the protein clearance among these four groups when estimated for the period between three minutes and 240 minutes Table 2.

Figure 4.

Dialysate to plasma concentration ratio (D/P) for urea (A) and total protein (B) versus dwell time. Symbols are: () 25 ml control group (Con25, N = 6); () 40 ml control group (Con40, N = 7); () 25 ml with 0.01% hyaluronan group (HA25, N = 6); () 40 ml with 0.01% hyaluronan group (HA40, N = 7). Significant differences (P < 0.05) were found for total protein between the Con25 and Con40 groups as well as between the two hyaluronan groups and their respective control groups.

Full figure and legend (34K)

DISCUSSION

The present study shows that increased peritoneal dialysate fill volume of 1.36% glucose dialysis fluid results in decreased net fluid removal because of increased peritoneal fluid absorption. The addition of hyaluronan to the dialysis solution significantly increased the net fluid removal by reducing the peritoneal fluid absorption, and could thus prevent the decrease in net fluid removal associated with the higher fill volume of 1.36% glucose dialysis solution.

Effect of increased peritoneal fill volume

Peritoneal fluid absorption is mainly driven by the intraperitoneal hydrostatic pressure (IPP)^9,33,34. The increased peritoneal fluid absorption rate associated with the increased IPP due to the higher intraperitoneal fill volume in the present study is in agreement with previous studies^3,8,9. However, our results show that direct lymphatic absorption assessed as the rate of appearance of intraperitoneally administered macromolecules (that is, RISA) in the blood (K_EB) was not significantly increased with increases in fill volume (Table 1 and Figure 2). A similar finding was reported in previous studies^3,8,9. Therefore, the increase in peritoneal fluid absorption rate associated with higher fill volume was mainly due to increased fluid absorption rate into the adjacent tissues of the peritoneal cavity as assessed by K_ET.

Although the K_E was significantly higher in the Con40 group as compared to the Con25 group, the transcapillary ultrafiltration rate (Q_u) was also significantly higher in the Con40 group. This is in agreement with our previous study using 3.86% glucose solution³. The increase in Q_u was mainly due to a better maintenance of the glucose concentration gradient in the high fill volume groups Figure 3, in agreement with previous studies^2,3,13. It is important to note that despite a higher transcapillary ultrafiltration rate in the higher fill volume groups, the net ultrafiltration volume was still significantly lower in the Con40 group (-4.2 1.3 ml) than in the Con25 group (-2.3 2.3 ml). This was due to the fact that the increased Q_u could not fully compensate for the increased K_E in the Con40 group when using 1.36% glucose dialysis solution. A similar finding was reported by Krediet et al, who found that the net ultrafiltration using 1.36% glucose dialysis solution was significantly lower when using 3 liters of fill volume compared to 2 liters of fill volume during a four-hour dwell study in CAPD patients, mainly due to increased peritoneal fluid absorption in the 3 liter solution group¹³. However, in a previous study in rats, we found that increases in dialysate fill volume using 3.86% glucose dialysis solution results in a higher net ultrafiltration despite a higher peritoneal fluid absorption rate, which was due to a higher Q_u with the 3.86% glucose solution counterbalancing the increase in K_E³. Therefore, we conclude that a decreased net ultrafiltration volume associated with higher dialysate fill volume (due to higher IPP and higher peritoneal fluid absorption) can be avoided if hypertonic glucose solutions are used.

Effect of hyaluronan on fluid transport

The significant decrease in K_E in the HA25 and HA40 groups compared to their respective control groups is in accordance with our findings in a previous study showing that an addition of hyaluronan to the dialysis fluid could markedly reduce peritoneal fluid absorption²³. In the previous study, we speculated that the observed effect of hyaluronan on peritoneal fluid absorption may be due both to the accumulation of a restrictive filter "cake" of hyaluronan chains at the tissue-cavity interface²³ as well as to a stabilizing effect on endogenous hyaluronan at the mesothelial cell surface³⁵. It is interesting to note that in the present study the magnitude of the decrease in peritoneal fluid absorption was much higher when the higher fill volume was used. The difference (0.15 ml/min) in K_E between the Con40 and the HA40 groups was much higher than the difference (0.07 ml/min) in K_E between the Con25 and the HA25 groups. As peritoneal fluid absorption is mainly driven by IPP, it is possible that raising IPP may transiently increase convective transport into the boundary, thereby raising the concentration and thickness of the hyaluronan layer, which could increase the resistance to the outflow of fluid from the peritoneal cavity. These results are similar to the observation made by McDonald and Levick, who found that an increase in the intra-articular pressure significantly increase the resistance of fluid outflow from the joint³⁶, the fluid outflow rate (from the joint) was in fact even lower when a significantly higher pressure was induced compared to the outflow rate observed under low intra-articular pressure³⁶. Under electron microscopy, they also observed that a hyaluronan membrane was formed at the tissue-cavity interface³⁶. In the present study, the difference in peritoneal fluid absorption rate between the two hyaluronan groups and their respective control groups was almost entirely due to the difference in the fluid absorption rate to adjacent peritoneal tissues as assessed by K_ET, suggesting a specific effect of hyaluronan on K_ET (and not K_EB). The similar K_E between the Con25 and the HA40 groups in our study suggests that intraperitoneal addition of hyaluronan could prevent the decreased net ultrafiltration volume associated with higher dialysate fill volume of 1.36% glucose solution.

Solute transport

The significantly slower decrease in dialysate glucose concentration (as reflected by D/D₀) as well as lower D/P of urea and total protein in the Con40 group compared to the Con25 group are in agreement with our previous study³. This is a result of the principle governed by the geometry of diffusion stating that equilibration of a solute occurs rapidly when the dialyzed solute diffuses into or from a relatively small volume, whereas relatively slower equilibration occurs in association with diffusion into a larger volume. As the diffusive mass transport coefficients (K_BD) for glucose and urea did not significantly increase with the increase in fill volume, the rate of maximal diffusive transport (as estimated by K_BD) to the volume that should be cleared (fill volume) decreased with high dialysate volume, resulting in a slower decrease in the dialysate glucose concentration as well as in lower D/P of urea.

Glucose absorption was unexpectedly slightly enhanced in the two hyaluronan groups during the initial part of the dwell, which is similar to our previous observation²³. The mechanism is not clear. However, it has been reported that the diffusion of glucose in a matrix gel containing hyaluronan was significantly increased³⁷. Hadler suggested that this increased diffusivity might be due to the interaction between glucose and the hyaluronan domain that facilitates glucose movement³⁸. However, further studies are needed to elucidate the mechanism(s) of the transiently increase in glucose absorption induced by the addition of hyaluronan to the dialysate.

The total protein concentrations in dialysate in the two hyaluronan groups were higher during the whole dwell as compared to their respective control groups. It is unlikely that the higher protein concentration was due to an increased transport of protein from the blood, as the difference in protein appearance in dialysate was observed during the initial three minutes only. In separate experiments, we did not find any significant difference in white blood cell counts in the effluents by adding hyaluronan to the dialysis fluid as compared to the control solution, suggesting that adding hyaluronan to the dialysate did not induce local inflammation. In addition, hyaluronan is an effective anti-inflammation substance, and it has been shown that hyaluronan could inhibit acute and chronic inflammation³⁹. The accuracy of the protein analytical assay was found to be unaffected by the presence of 0.01% hyaluronan in vitro (data not shown). There was no significant increase in protein clearance in the HA groups in our study as estimated from three minutes, which is in agreement with previous observations³. Therefore, we speculate that the rapid increase in protein concentration found during the initial three minutes of the dwell may be due to a competition of hyaluronan with surface proteins for binding onto the mesothelial cell surface.

The significant increase in urea clearance in the high fill volume groups is not unexpected. However, it is important to note that adequacy of dialysis is not only a matter of removing enough small solutes, but also a matter a removing enough fluid^40,41. In fact, inadequate fluid removal and inadequate blood pressure control are common in CAPD patients^42,43, and may contribute to cardiovascular disease, which is the main cause of death in PD patients⁴³. Therefore, if the increase in urea clearance with high dialysate fill volume is associated with a decrease in net fluid removal, this represents an important clinical problem. The addition of hyaluronan to dialysate may be a way to overcome this problem, as the addition of hyaluronan resulted in both increased fluid removal and increased urea clearances.

In summary, our results suggest that (1) An increase in dialysate fill volume using 1.36% glucose dialysis solution results in higher intraperitoneal hydrostatic pressure and higher peritoneal fluid absorption rate, and therefore in fact results in lower net ultrafiltration despite a higher transcapillary ultrafiltration rate. (2) Intraperitoneal addition of hyaluronan significantly decreases the peritoneal fluid absorption rate. The decreasing effect was more significant when high fill volume was used, reflecting perhaps a possible formation of a "hyaluronan filter cake" at the peritoneal cavity-tissue interface. (3) In general, the peritoneal diffusive mass transport coefficients did not change with different fill volume or by adding hyaluronan; however, small solute clearances increase markedly with increases in fill volume and by adding hyaluronan to the dialysate due to the higher drainage volume.

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Acknowledgments

This study was supported by a grant from Baxter Healthcare Corporation, McGaw Park, Illinois, USA. We thank Dr. Torvard C. Laurent for support and constructive criticism of this work, and Ms. Monica Eriksson for technical assistance.