The Beginning of Icodextrin

Correspondence to: C.D. Mistry, Peterborough District Hospital, Thorpe Road, Peterborough PE3 6DA United Kingdom. chandra.mistry@btopenworld.com Received 27 October 2009; accepted 9 September 2010. In the history of peritoneal dialysis (PD), 1976 marked a significant step forward when Popovich and Moncrief revolutionized the practice by introducing the concept of equilibration PD and extending the duration of dwell time to 4 – 10 hours (1). Despite this fundamental change in the practice of PD, the basic principle used to generate osmotic forces across the peritoneum remained unaltered. This principle relied on the traditional concept of osmotic flow across an “ideal” semipermeable membrane, necessitating making dialysis solution hypertonic to plasma with the addition of glucose as osmotic agent. Unfortunately, not being an “ideal” semipermeable membrane but being partially permeable to solutes, the peritoneum allows rapid absorption of glucose with progressive dissipation of the osmotic gradient and ultrafiltration of short duration. While this is of little significance during short dwell exchanges (30 – 60 minutes’ dwell in intermittent PD), it is not the case for long exchanges, such as in continuous ambulatory PD (CAPD) and automated PD, where reabsorption of initially ultrafiltered peritoneal fluid occurs. In addition, the continuous daily absorption of glucose aggravates longterm metabolic complications, including hyperlipidemia and obesity (2,3). Even as early as the 1980s there was clear recognition for an alternative osmotic agent that would minimize metabolic derangements and provide the ultrafiltration profile to suit long dwell exchanges. A range of different macromolecules was evaluated based on the simplistic concept that large molecular weight (MW) agents are less readily absorbed through the peritoneum and are likely to produce sustained ultrafiltration while reducing metabolic complications. Early investigations clearly identified the problems associated with use of nonphysiological hyperviscous macromolecules and defined the need for a neutral substance that is soluble, nonallergenic, and readily metabolized (3). Glucose polymer (GP), derived from hydrolyzed cornstarch, seemed a natural contender and several groups already held patents of diverse MW fractions. Among them, the Abbott group led the way by studying a narrow MW fraction (MW 1000 Da) in both animals (4) and humans (5). In Manchester, we were well placed to explore the potential of this novel agent as considerable experience had been developed while investigating GP (Caloreen) as an intravenous high-energy nutrient source in the management of patients with renal (6) and hepatic failure (7). We worked closely in collaboration with Jerry Milner, the holder of the patent for Caloreen, Fisons Pharmaceutical, who had established expertise in fractionating GP technology, and J. Fox, Department of Biochemistry, University of Birmingham, who had extensive experience in methods of carbohydrate analysis. For the initial clinical studies carried out in July 1983, we utilized a readily available dextrin formulation (Caloreen) with a bimodal MW distribution consisting of a 67% “low” MW fraction (chain length 12 glucose units); weight average MW (Mw) was 7000 Da and number average MW (Mn) was 960 Da. In contrast to glucose solution, predicting osmotic performance of a polydisperse GP sample with a relatively unknown peritoneal permselectivity proved difficult. Our preliminary studies suggested that 5% (52 mmol/L) and 10% (104 mmol/L) GP solutions were probably comparable to 1.36% (76 mmol/L) and 3.86% (214 mmol/L) glucose respectively (8). The first formal Phase 1 study, using solutions containing 5% (52 mmol/L) and 10% (104 mmol/L) of this GP formulation over a 6-hour dwell, was exciting and