Icodextrin metabolism in peritoneal dialysis : Clinical and experimental studies

Abstract: Icodextrin (ICO, or polyglucose) is an effective osmotic agent for peritoneal dialysis (PD) patients (pts). ICO is a soluble polymeric form of glucose with an average molecular 'weight range from 13,000 to 19,000 dalton. Glucose is absorbed from the peritoneal cavity by diffusion. For ICO, however, the diffusive transport is limited, and absorption occurs primarily by convective transport. As a result the osmotic pressure created by ICO is relatively constant and ultrafiltration (UF) is sustained throughout a long dwell. Approximately 20 % to 40 % of the administered ICO is absorbed from the peritoneal cavity and is metabolized by alpha-amylase to yield ICO metabolites. The total amylase activity in plasma is reported to be reduced in ICO users due to both interference with the substrate and a possible real decreased. The aim of this study was to use HPLC with a modem gel-filtration media to determine high (HMW) and low (LMW) molecular weight ICO molecules in dialysate and plasma in P1) pts on treatment with ICO, to investigate ICO metabolism in plasma and dialysate, and to investigate possible relationships between the production of these compounds and alpha-amylase activity in serum. Similar studies were conducted in non-uremic rats undergoing chronic PD. Paper I. We evaluated the feasibility of a gel-filtration HPLC method for the determination of HMW and LMW ICO molecules in dialysate and plasma in PD pts, and to validate the results, samples were exposed to enzymatic hydrolysis. Absorption of ICO from the peritoneal cavity during the long dwell was 39 % of the initial amount. In dialysate, the largest HMW fractions decreased, whereas the middle molecules and LMW metabolites showed a relative increase. The plasma concentration of ICO metabolites was significantly higher and alpha-amylase activity significantly lower, in ICO groups. Paper II. To validate an assay for measurement of total alpha-amylase activity in serum containing ICO degradation products, three experiments were performed: 1) Supplementation of ICO up to 75 % of ICO did not interfere with the alpha-amylase assay. 2) Supplementation of synthetic alphaamylase: synthetic alpha-amylase was fully recovered. 3) Altering the concentration of the assay's substrate; interference of ICO could be shown when the assay was dramatically modified. This study shows that true values of alpha-amylase can be measured in samples containing ICO degradation products. Paper III. alpha-Amylase activity in plasma and dialysate, and the degradation of ICO during chronic PD was investigated in 23 nonuremic rats with implanted peritoneal catheter. A 4-hour dwell with ICO solution was performed twice, at days 10 and 21. Plasma samples were taken at 0 time and at the end of the dwell, and dialysate samples at 3, 15, 30, 60, 90, 120, and 240 min. a- alpha-Amylase OBS activity was much higher in rats than in humans. ICO metabolism was not influenced by chronic exposure to ICO. The rat is not an ideal species to study ICO metabolism; however, for certain aspects of ICO metabolism such as the intraperitoneal metabolism, may be useful. We conclude that accurate analysis of HMW fractions in dialysate and LMW ICO metabolites in plasma and dialysate can be achieved by gelfiltration HPLC with two different columns. This method can be used to study the complex pattern of changes of ICO and its metabolites in plasma and dialysate in PD pts, due to the combined impact of alpha-amylase activity, and diffusive and convective transport.