Icodextrin Metabolism and Alpha-Amylase Activity in Nonuremic Rats Undergoing Chronic Peritoneal Dialysis

Abstract

Objective To study the metabolism of icodextrin and α–amylase activity following daily exposure to dialysis solutions containing either glucose or icodextrin as osmotic agent in rats. Methods Male Wistar rats with implanted peritoneal catheters were infused twice daily for 3 weeks with 20 mL 7.5% icodextrin-based peritoneal dialysis fluid (IPDF; ICO group, n = 12) or 3.86% glucose-based peritoneal dialysis fluid (GLU group, n = 11). A 4-hour dwell study using 30 mL IPDF was performed on day 10 (D1) and day 21 (D2) in both the ICO and the GLU groups. Radiolabeled serum albumin (RISA) was used as a macromolecular volume marker. Dialysate samples were collected at 3, 15, 30, 60, 90, 120, and 240 minutes. Blood samples were drawn before the start and at the end of the dwell. Results During all dwell studies, the dialysate concentrations of total icodextrin decreased due to decrease in high molecular weight (MW) fractions, whereas there was a marked increase in icodextrin low MW metabolites. α–Amylase activity increased in dialysate and decreased in plasma. About 60% of the total icodextrin was absorbed from the peritoneal cavity during the 4-hour dwells. Low MW icodextrin metabolites were present in the dialysate already at 3 minutes, and maltose (G2), maltotriose (G3), maltotetraose (G4), and maltopentaose (G5) increased progressively, reaching maximum concentrations at 60 minutes. Maltohexaose (G6) and maltoheptaose (G7) were also detected already at 3 minutes but did not change significantly during the dwells. During the two 4-hour dwell studies (D1 and D2), the concentrations of total icodextrin and icodextrin metabolites and α–amylase activity in dialysate did not differ between the ICO and GLU groups, during either D1 or D2. No icodextrin metabolites were detected in plasma at the end of the dwells. α–Amylase activity in the dialysate increased six- to eightfold whereas plasma α–amylase activity decreased by 21% – 26% during the two 4-hour dwells in both the ICO and the GLU groups; there were no significant differences between the ICO and the GLU groups during either D1 or D2. α–Amylase activity in the dialysate correlated strongly with the disappearance rate of icodextrin from the peritoneal cavity during the 4-hour dwells, and with the concentrations of G2, G3, G6, and G7 in dialysate. Conclusions The decline in the dialysate concentrations of high MW fractions and the increase in low MW metabolites of icodextrin suggest intraperitoneal α–amylase mediated the metabolism of icodextrin and the transport of predominantly the smaller icodextrin metabolites from dialysate. However, no icodextrin could be detected in plasma, suggesting that it was metabolized and excreted by the kidney in these nonuremic rats. In contrast to uremic peritoneal dialysis patients, chronic exposure to IPDF did not seem to further affect α–amylase activity or icodextrin metabolism. The much higher α–amylase activity in plasma and dialysate in rats than in humans explains the much more rapid metabolism of icodextrin in rats compared with peritoneal dialysis patients.

Ultrafiltration Characteristics of Glucose Polymers with Low Polydispersity

“…First, the plasma and dialysate alpha-amylase activity reported here is less than that reported in a rat model of PD (13), suggesting that, in dwell studies, glucose polymer metabolism is lower in the rabbit than in the rat. On the other hand, dialysate alpha-amylase activity in the rabbit significantly exceeded dialysate levels measured in PD patients (12).…”

“…Rabbit models have been used for decades to evaluate PD solutions and peritoneal transport (15)(16)(17)(18)(19), but no such evaluations of dialysis solutions containing glucose polymers as osmotic agents have been published, except for our previous work in abstract form (10). There are two advantages to using a rabbit model, compared with a rat model, to evaluate dialysis solutions containing glucose polymers as osmotic agents: • The kinetics of UF in rat models of PD using icodextrin as the osmotic agent have been reported to differ significantly from those in human PD (13,(20)(21)(22).…”

“…The target polydispersities and molecular weights were approximated, although the polydispersity of the 6K glucose polymer was higher than targeted. The molecular weight distribution of the glucose polymers was independently determined by García-López and colleagues (12)(13)(14); Figure 2 shows the results from those determinations. Table 2 shows the characteristics of the group A and B rabbits at the beginning of each dwell study.…”

Mechanisms of Crystalloid versus Colloid Osmosis across the Peritoneal Membrane

“…Studies in rat models of PD have raised the issue of high intraperitoneal levels of a-amylase, potentially influencing the breakdown and metabolism of icodextrin. [30][31][32][55][56][57] The a-amylase activity measured in the peritoneal effluent of our mouse models yielded values closer to those in patients receiving PD than in rats. In addition, the remaining icodextrin concentration in the dialysate (approximately 40 mg/ml) and the profile of lowmolecular-mass icodextrin metabolites (with smaller polymers [G2 to G4] predominating over the larger ones [G5 to G7]) observed in mice at the end of the dwells were all similar to what is reported in patients receiving PD.…”

“…Total icodextrin in the dialysate was measured by enzymatic hydrolysis with amyloglucosidase (Sigma-Aldrich, Saint-Louis, MO), icodextrin metabolites were determined in the dialysate of mice exposed to 7.5% icodextrin using a weak anion-exchange column (BioBasic AX; 15034.6 mm, 5 mm; Thermo Electron, Woburn, MA) and a refractive index detector, and total HMW fractions were estimated as the difference between total icodextrin and LMW G2-G7 fractions, as previously described. [30][31][32] The amount of carbohydrates absorbed from the peritoneal cavity was calculated as the difference between the mass of carbohydrates (glucose and icodextrin) infused into the peritoneal cavity and the mass removed.…”