Icodextrin

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Abstract
Icodextrin (Extraneal®) is a high molecular weight glucose polymer developed specifically for use as an alternative osmotic agent to dextrose during the once-daily long-dwell exchange in peritoneal dialysis (PD). Isosmotic 7.5% icodextrin solution induces transcapillary ultrafiltration (UF) by a mechanism resembling ‘colloid’ osmosis (unlike hyper-osmolar dextrose-based solutions, which induce UF by crystalline osmosis). In addition, absorption of icodextrin from the peritoneal cavity is relatively slow compared with that of dextrose; this results not only in UF of longer duration, but also a lower carbohydrate load compared with medium (2.5%) and strong (4.25%) dextrose exchanges. In randomised clinical trials of up to 2 years in duration, administration of icodextrin for the long (8- to 16-hour) overnight exchange in continuous ambulatory peritoneal dialysis (CAPD) or daytime exchange in automated peritoneal dialysis (APD) produced net UF which exceeded that with 1.5% and 2.5% dextrose solutions (thereby improving fluid balance), and was equivalent to that with 4.25% dextrose solution. Icodextrin also increased peritoneal clearances of creatinine and urea nitrogen compared with 2.5% dextrose solution. The increase in UF volume with icodextrin was enhanced in CAPD patients with high peritoneal membrane permeability (i.e. high and high-average transporters), maintained in the small number of patients followed-up for 2 years and sustained during episodes of peritonitis. Icodextrin reduced the percentage of patients with net negative UF in contrast to 1.5% and 2.5% dextrose and, in noncomparative studies, extended PD technique survival in patients who had failed dextrose-based dialysis. The use of icodextrin was also associated with some symptomatic improvements and health-related quality of life advantages, and no adverse effect on patient survival, compared with dextrose, although confirmation of these findings is ideally required in appropriately designed studies. The tolerability of icodextrin was generally similar to that of dextrose-based solutions in controlled clinical trials, although there was an approximate three-fold increase in the risk of new skin rash (5.5% vs 1.7%). However, reports of severe cutaneous hypersensitivity reactions remain rare; this possibility should not preclude the use of the polymer. Conclusion: 7.5% icodextrin solution offers the first feasible alternative to conventional dextrose solutions for the once-daily long-dwell exchange in PD. It is effective, generally well tolerated and appears to be most useful in situations of reduced or inadequate UF with dextrose, including in high and high-average transporters, during episodes of peritonitis and patients who have failed dextrose-based dialysis. Icodextrin, a starch-derived, water-soluble, glucose polymer (average molecular weight 16.8kDa) linked predominantly by α1–4 glucosidic bonds, induces trans-capillary ultrafiltration (UF; removal of excess fluid from the plasma) by a mechanism resembling ‘colloid’ osmosis. Thus, icodextrin-based peritoneal dialysis (PD) solutions can be iso-osmotic with respect to normal plasma, unlike hyper-osmotic dextrose-based solutions, which produce UF by crystalline osmosis. Intraperitoneal administration of PD solution containing 7.5% icodextrin provides sustained UF throughout the once-daily long-dwell exchange (8–16 hours) in patients treated with continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD); the effect on UF is immediate with the first exchange. UF volumes with icodextrin are equivalent to those with ‘strong’ (4.25%) dextrose solutions; compared with ‘weak’ (1.5%) and ‘medium’ (2.5%) dextrose solutions, icodextrin increases UF and improves fluid balance. Interestingly, in a 4-month randomised multicentre trial, treatment with icodextrin, but not 1.5% dextrose, was associated with a significant 5% reduction in left ventricular hypertrophy, an effect that was unrelated to changes in volume status or blood pressure. Due to the relatively slow rate of absorption of icodextrin from the peritoneal cavity (which accounts for the prolonged UF effect) the carbohydrate load per exchange is lower than that with 2.5% and 4.25% dextrose solutions. Beneficial effects of icodextrin on insulin sensitivity and plasma lipids (significant reductions in total and low-density lipoprotein cholesterol levels) compared with dextrose have also been observed in some studies. These reports notwithstanding, the incidences of hyperglycaemia (5% vs 4%) and hypercholesterolaemia (2% vs 2%) were similar for icodextrin and dextrose in a pooled analysis of data from controlled clinical trials. Preclinical data suggesting that icodextrin may be a more biocompatible osmotic agent than dextrose have recently received some clinical support. Specifically, icodextrin appeared to have a less deleterious effect on membrane function, especially compared with 2.5% and 4.25% dextrose, in a 2-year prospective study in 177 anuric APD patients. However, neither icodextrin nor 1.5–4.25% dextrose solutions had clinically meaningful effects on peritoneal membrane characteristics during 1–2 years of treatment in randomised studies of nonanuric CAPD patients. Icodextrin is absorbed at a constant rate from the peritoneal cavity, mostly via lymphatic pathways. The amount of icodextrin absorbed thus depends on the dwell time; it represents approximately 40% of the administered dose after a 12-hour exchange. Up to 80% of the absorbed icodextrin dose is eventually metabolised, first by circulating α-amylases and then by tissue maltases, into glucose; the remaining 20% is eliminated via the urine (in direct proportion to the level of residual renal function) or in the dialysate. The plasma profile of icodextrin and its three main metabolites (maltose, maltotriose, and maltotetraose)...