Icodextrin metabolism in peritoneal dialysis : Clinical and experimental studies

Sammanfattning: Icodextrin is a glucose polymer which is used as osmotic agent to provide sustained ultrafiltration (UF) during the long (8-16 hours) dwell in end-stage renal disease patients undergoing peritoneal dialysis (PD). The aims of this thesis were to study: the metabolism of icodextrin in the peritoneal cavity and in the circulation of PD patients and non-uremic rats, the role of alpha-amylase in its hydrolysis, and the rate of breakdown of a synthetic maltoheptaose (G7) ex vivo which we propose as a novel measure of amylase mediated oligosaccharide metabolism. Study I. Gel-filtration HPLC was applied to determine high and low molecular weight icodextrin molecules in dialysate and plasma from PD patients using glucose solution or icodextrin (after the first dwell or chronically). Total hydrolysis of the samples was used to validate the results. 39 % of the infused icodextrin was absorbed from the peritoneal cavity during the long dwell. The plasma concentration of icodextrin metabolites was significantly higher and alpha-amylase activity significantly lower in the icodextrin groups. Study II. An assay for measurement of total alpha-amylase activity in serum containing icodextrin degradation products was validated. The study demonstrated that the low values of plasma alpha-amylase activity in PD patients using icodextrin are correctly determined. Study III. In 23 non-uremic rats undergoing chronic PD using either glucose- or icodextrinbased dialysis solutions, a 4-hour dwell with icodextrin was performed twice, at days 10 and 21. There was a significant decrease in amylase activity in plasma (which is much higher than in humans) and an increase in dialysate. About 60 % of the infused icodextrin was absorbed from the peritoneal cavity at the end of the dwell. No icodextrin metabolites were detected in plasma at the end of the dwell. Study IV. The rate of degradation of G7 in plasma from healthy controls, and PD patients using only glucose solution or glucose in combination with icodextrin was investigated ex vivo. Samples were spiked with G7 and/or synthetic amylase, and incubated 4 hours at 37oC. The G7 degradation rate was lower in plasma from icodextrin patients but it was also reduced in PD patients using glucose, in spite of the higher amylase activity, as compared with the controls. This suggests that the amylase mediated carbohydrate metabolism is reduced in PD patients. It is possible that this could contribute to reduced hyperglycemic changes, especially in patients using icodextrin. Study V. When investigating also pre-dialysis (PreD) and hemodialysis (HD) patients, we found that the rate of degradation of G7 did not differ from the controls. Amylase activity was increased in the PreD, HD and GLU patients, and decreased in the ICO patients. The rate of G7 degradation per unit of amylase activity was reduced in PreD and GLU patients. The rate of G7 degradation was related to the endogenous amylase activity. These findings suggest that the amylase mediated oligosaccharide metabolism is altered in uremic patients, although this needs to be confirmed in larger studies. Study VI. The relationship between the efficacy of icodextrin in changing UF, fluid status and residual urine volume versus the concentration of plasma icodextrin metabolites was investigated. There was no relationship between plasma concentrations of icodextrin metabolites and any of the other clinical parameters, including change in daily UF, urine volume, fluid or inflammatory status. Icodextrin was not associated with a greater fall in urine output despite its larger effect on the volume of extra-cellular fluid.