Effects of intraperitoneal hyaluronan on peritoneal fluid and solute transport in peritoneal dialysis patients.

BACKGROUND: Hyaluronan (HA) is a glycosaminoglycan found in connective tissues and tissue spaces, including the peritoneal cavity. In vivo studies in a rat model of peritoneal dialysis (PD) have shown that addition of HA to PD solution during an intraperitoneal dwell can alter peritoneal fluid transport and protect the peritoneal membrane from the effects of inflammation and repeated infusions of dialysis solution. The current study sought to evaluate the safety of intraperitoneal HA and its effect on peritoneal fluid and solute transport when administered during a dialysis dwell in humans. METHODS: 13 PD patients were enrolled in a prospective, randomized crossover study involving three dialysis treatments using the following PD solutions: (1) a commercially available PD solution (Dianeal PD-4, 1.36% glucose; Baxter Healthcare Corporation, Alliston, Ontario, Canada); (2) Dianeal PD-4 containing 0.1 g/L HA, and (3) Dianeal PD-4 containing 0.5 g/L HA. Each 6-hour dialysis exchange was separated from the other exchanges by a 2-week washout period. Radioiodinated human serum albumin (RISA) was administered with the dialysis solution to evaluate intraperitoneal volume, net ultrafiltration (UF), and fluid reabsorption. Peritoneal clearances, dialysate/plasma ratios (D/P), and mass transfer area coefficients (MTACs) were determined for sodium, urea, creatinine, albumin, and glucose. Safety was evaluated by monitoring adverse events and changes in serum chemistries. Ten patients completed all three dialysis exchanges and two additional patients completed at least one treatment exchange. RESULTS: There were no reported adverse events related to HA administration and no significant changes in serum chemistries. There were no significant differences in net UF or peritoneal volume profiles among the three treatments. Mean net UF calculated using residual volumes, estimated by RISA dilution, tended to be slightly higher during treatment with solution containing 0.1 g/L HA and 0.5 g/L HA [74 +/- 86 (SE) and 41 +/- 99 mL, respectively] compared to control treatment (-58 +/- 129 mL). Although not statistically significant, there was a trend toward decreased fluid reabsorption during treatment with HA. Solute clearances, D/P ratios, and MTACs were similar for the three treatments. Serum levels of HA were also unaffected by the two treatment solutions. CONCLUSIONS: These data support the acute safety of HA when administered intraperitoneally with the dialysis solution to PD patients. Due to the small sample size and variability in net UF and fluid reabsorption, statistically significant differences were not demonstrated for these parameters. However, a trend toward decreased fluid reabsorption was observed, suggesting that HA may act by a mechanism similar to that observed in animal studies. Further studies are necessary to evaluate whether the beneficial effects of HA observed in animal studies can be shown in humans.

Pharmacokinetics of icodextrin in peritoneal dialysis patients.

UNLABELLED: Pharmacokinetics of icodextrin in peritoneal dialysis patients. BACKGROUND: Icodextrin is a glucose polymer osmotic agent used to provide sustained ultrafiltration during long peritoneal dialysis (PD) dwells. A number of studies have evaluated the steady-state blood concentrations of icodextrin during repeated use; however, to date the pharmacokinetics of icodextrin have not been well studied. The current study was conducted to determine the absorption, plasma kinetics and elimination of icodextrin and metabolites following a single icodextrin exchange. METHODS: Thirteen PD patients were administered 2.0 L of solution containing 7.5% icodextrin for a 12-hour dwell. Icodextrin (total of all glucose polymers) and specific polymers with degrees of polymerization ranging from two to seven (DP2 to DP7) were measured in blood, urine and dialysate during the dwell and after draining the solution from the peritoneal cavity. RESULTS: A median of 40.1% (60.24 g) of the total administered dose (150 g) was absorbed during the 12-hour dwell. Plasma levels of icodextrin and metabolites rose during the dwell and declined after drain, closely corresponding to the one-compartment pharmacokinetic model assuming zero-order absorption and first-order elimination. Peak plasma concentrations (median C peak = 2.23 g/L) were observed at the end of the dwell (median Tmax = 12.7 h) and were significantly correlated with patients' body weight (R2 = 0.805, P < 0.001). Plasma levels of icodextrin and metabolites returned to baseline within 3 to 7 days. Icodextrin had a plasma half-life of 14.73 hours and a median clearance of 1.09 L/h. Urinary excretion of icodextrin and metabolites was directly related to residual renal function (R2 = 0.679 vs. creatinine clearance, P < 0.01). In the nine patients with residual renal function, the average daily urinary excretion of icodextrin was 473 +/- 77 mg per mL of endogenous renal creatinine clearance. Icodextrin metabolites DP2 to DP4 were found in the dialysate of subsequent dextrose exchanges, contributing to their elimination from blood. Changes in intraperitoneal concentrations of icodextrin metabolites during the dwell revealed a dual pattern, with a progressive rise in the dialysate concentration of smaller polymers (DP2 to DP4) and a progressive decline in the dialysate concentrations of the larger polymers (DP5 to DP7), suggesting some intraperitoneal metabolism of the glucose polymers. This increase in dialysate metabolite levels, however, did not contribute significantly to dialysate osmolality. In addition, some diffusion of maltose (DP2) from blood to dialysate may have occurred. There were no changes in serum insulin or glucose levels during icodextrin administration, indicating that icodextrin does not result in hyperglycemia or hyperinsulinemia as occurs during dextrose-based dialysis. Serum sodium and chloride declined in parallel with the rise in plasma levels of icodextrin, supporting the hypothesis that these electrolyte changes are the result of the increased plasma osmolality due to the presence of icodextrin metabolites. CONCLUSIONS: The pharmacokinetics of icodextrin in blood following intraperitoneal administration conforms to a simple, single-compartment model that can be approximated by zero-order absorption and first-order elimination. A small amount of intraperitoneal metabolism of icodextrin occurs but does not contribute significantly to dialysate osmolality. The metabolism of absorbed icodextrin and the resultant rise in plasma levels of small glucose polymers (DP2 to DP4) do not result in hyperglycemia or hyperinsulinemia, but may result in a small decrease in serum sodium and chloride.