Icodextrin in peritoneal dialysis

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Icodextrin in peritoneal dialysis

The Story of Icodextrin – a historical perspective

From a powder (Glucose Polymer) to a PD solution (Icodextrin)

Good Collaboration – Academic unit and Industry

By Prof Ram Gokal and Dr Chandra Mistry

How did it all start?

It all started with the work done at the Manchester Royal Infirmary with glucose polymers. Caloreen, a glucose polymer which did not taste sweet and could be excreted, became of interest to nephrologists because of the modified Giovanetti diet which consultant nephrologist Geoffrey Berlyne had promoted in Manchester. This diet was designed to provide sustenance for patients with advanced renal failure who today would be on dialysis but could not then find dialysis places. The diet needed a calorie source which was not sweet.   Geoffrey was in touch with an entrepreneur, Gerry Milner, a scientist with a background in the food industry, who had decided to specialise in developing foodstuffs for patients with various special dietary needs.  He found a glucose polymer which was broken down in the intestine to glucose and maltose, and which fulfilled the calorie  requirement for the modified Giovanetti diet.  After Geoffrey Berlyne  left Manchester, Gerry Milner and Netar Mallick remained in contact and did some studies of the  kinetics of Caloreen after intravenous administration.   Netar understood that there was need for a non-glucose osmotic agent for CAPD, and realised that Caloreen had potential, given the limitations of high glucose as the osmotic agent, especially in diabetics. One of Netar’s challenges had been to get more junior staff fir the MRI renal unit; he was allocated a lecturer and a senior registrar. There were also resources for a research registrar. Chandra Mistry came to this post and took up the CAPD/Caloreen challenge, and then in 1980 Ram Gokal joined the unit .

The rest is history and Caloreen, now of course known as icodextrin remains a mainstay of clinical PD practice.

 Clinical research studies at the MRI – Chandra Mistry and Ram Gokal

A  basic principle of PD is  is to achieve ultrafiltration  by generating osmotic forces across the peritoneum.  To generate osmotic flow across an “ideal” semipermeable membrane, necessitates making the dialysis solution hypertonic to plasma, usually achieved by  the addition of glucose as the 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 minute’ dwell in intermittent PD), it is not the case for long exchanges, as in CAPD and automated PD (APD), where reabsorption of initially ultrafiltered peritoneal fluid occurs. In addition, the continuous daily absorption of glucose potentiates long-term metabolic complications.

Even as early as the 1980s there was the need was recognised  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. Glucose polymer (GP), derived from hydrolyzed cornstarch, seemed a natural contender and several groups already held patents for diverse MW fractions. Among them, the Abbott group and Jim Winchester, led the way by studying MW fraction (MW 1000 Da) in both animals and humans (Rubin J, Jones Q, Planch A, Bower J, Klein E. Substitution of a starch polymer for glucose in peritoneal dialysis. Nephron 1985; 39:40–6.  Winchester JF, Stegink LD, Ahmad S, Gross M, Hammeke M, Horowitz JF, et al. A comparison of glucose polymer and dextrose as osmotic agents in CAPD. In: Maher JF, Winchester JF, eds. Frontiers in Peritoneal Dialysis. New York: Field, Rich and Associates; 1986: 231–40). This fraction was not purused further because of accumulation of maltose.

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 and hepatic failure ( Berlyne GM, Booth EM, Brewis RA, Mallick NP. A soluble glucose polymer for use in renal failure and calorie-deprivation states. Lancet 1969; 1:689–92. . Ricketts CR. Sugars and dextrins for dietary use. In: Mallick NP, ed. Glucose Polymer in Health and Disease. The Role of Caloreen. Lancaster: MTP Press; 1977: 45–52). We worked closely in collaboration with Gerry Milner, the holder of the patent for Caloreen, with Fisons Pharmaceutical, who had established expertise in fractionating GP technology, and with J. Fox, Department of Biochemistry, University of Birmingham, who had extensive experience in methods of carbohydrate analysis.

 Studies at  MRI

These are all outlined in the paper by Chandra Mistry in PD International in 2011 Mistry C PDI 2011(Chandra Mistry 2011 Perit Dial Int. 2011 Mar;31 Suppl 2:S49-52). Readers are directed to this very informative paper that meticulously outlines the history, the trials and tribulations, the links and collaboration with many industry partners and the outcomes from the studies leading to its current use in clinical practice. There were many phases as the studies progressed and Chandra had to overcome many issues, related to the composition of the polymer profile to achieve optimum UF and minimal absorption of maltose and GP breakdown moieties.

A glucose Polymer with a bimodal MW distribution


Initial feasibility studies. Note the sustained ultrafiltration over a 16 hour dwell with 7.5% icodextrin compared to three different glucose concentrations

These studies showed for the first time that GP probably exerted its effect by a mechanism resembling colloid osmosis and therefore could be adapted as a novel osmotic agent in CAPD. Following refinement of the manufacturing process, our clinical studies progressed rapidly and demonstrated superior ultrafiltration with 5% iso-osmolar GP solution for dwells up to 12 hours. ( Mistry CD. Glucose polymer as an osmotic agent in continuous peritoneal dialysis [Thesis]. London: University of London; 1989.  Mistry CD, Gokal R, Mallick NP. Glucose polymer as an osmotic agent in continuous peritoneal dialysis (CAPD). In: Maher JF, Winchester JF, eds. Frontiers in Peritoneal Dialysis. New York: Field, Rich and Associates; 1986: 241–8. Mistry CD, Fox JE, Mallick NP, Gokal R. Circulating maltose and isomaltose in chronic renal failure. Kidney Int 1987; 32(Suppl 22):S210–14)

With a change in the manufacturing process from solvent-based to membrane-based fractionation, we obtained a slightly larger (Mw 22000 Da; Mn 7000 Da) but more reproducible fraction. A 7.5% solution (10.7 mmol/L) yielded ultrafiltration like the previous 5% GP solution but was hypo-osmolar (277 mOsm/kg) to uremic serum. This was the first clinical demonstration of osmotic flow against the conventional osmolality gradient using a hypo-osmolar dialysate that finally consolidated the role of GP as a colloid osmotic agent ( Mistry CD, Gokal R. Can ultrafiltration occur with a hypoosmolar solution in peritoneal dialysis?: The role for ‘colloid’ osmosis. Clin Sci 1993; 85:495–500).

Furthermore, it provided a wonderful opportunity to prove the hypothesis that ultrafiltration profiles over varying dwell times could be optimized using different proportions of colloid and crystalloid agents combined in an iso-osmolar dialysate (Mistry CD, Bhowmick B, Ashnam R, Uttley L. Clinical studies of new icodextrin formulations. Perit Dial Int 1994; 14(Suppl 2):S55–7.).

We were fortunate in our collaboration with Fisons Pharmaceutical, who successfully fractionated Caloreen into two component parts using the conventional solvent-based fractionation process. The high MW fraction of GP was isolated, with 95% of the profile containing ultrafiltration with very little day-to-day variation: maltose levels reached steady state within 6 days without apparent tissue accumulation (Mistry CD, Gokal R. Icodextrin in peritoneal dialysis: early development and clinical use. Perit Dial Int 1994; 14(Suppl 2):S13–21.).

While this was reassuring, the  question remained whether these elevated but steady state levels would be harmful in the long term.

Early commercial  developments – ML Laboratories

Gerry Milner, in partnership with Kevin Leech, an entrepreneur, formed a new biopharmaceutical company: M L Laboratories plc. In 1988, Fisons withdrew from the project and M L Laboratories   set up a small manufacturing unit at Wavertree Technology Park in Liverpool, UK, with the capacity to manufacture the product by a new process involving membrane fractionation. The opening of the plant was performed by Dennis Healey, Secretary of State for Health.

Opening of the ML manufacturing plant, Liverpool, 1989

L to R: Chandra Mistry, Rt. Hon Denis Healey MP, ? , Ram Gokal, Netar Mallick

Long term studies

Next, we undertook a 3-month study the favourable results of which paved the way for the MIDAS study. (Mistry CD, Gokal R. A single daily overnight (12 hr dwell) use of 7.5% glucose polymer (Mw 18,700; Mn 7,300) + 0.35% glucose solution: a 3 month study. Nephrol Dial Transplant 1993; 8:443–47),

In 1991, M L Laboratories embarked on the MIDAS study a randomized, controlled, multicenter trial  to compare over 6  months the efficacy and safety of icodextrin with conventional glucose solutions in CAPD involving 11 centers and 209 patients

The MIDAS trial  used the optimal GP fraction (Mw 22000 Da; Mn 7000 Da) for ultrafiltration that minimized maltose accumulation, which  was subsequently used in all long-term studies. This fraction, originally referred to as “dextrin 20,” was later renamed “icodextrin,” from the Greek icosa, meaning twenty. (Mistry CD, Gokal R, Peers MA; Midas Study Group. A randomized multicenter clinical trial comparing isosmolar dextrin 20 with hyperosmolar glucose solutions in continuous ambulatory peritoneal dialysis (CAPD): a six month study. Kidney Int 1994; 46:496–503).

Later commercial developments

Icodextrin received a product license in the UK in January 1993, and European marketing approval in March 1994. As part of the licensing process, M L Laboratories commissioned Professor David Kerr to write an independent expert report. Chris Winearls recalls:

“Prof David Kerr had agreed in 1992 to write the expert report to support the  licensing of icodextrin but did not do so in a timely fashion. He was admitted to CCU with an inferior MI at the Hammersmith Hospital a few days before the report was due.  He tried to write  it while all hooked up to monitors, but Prof Celia Oakley, the formidable cardiologist, confiscated the files and his Dictaphone forbidding him to work for 4 weeks.  I returned home at midnight from my FRCP ceremony to be greeted by wife to say a Prof Davies from  Clinical  Pharmacology at the RPMS wanted me to phone him no matter how late. He explained the predicament. He had an interest in Icodextrin and its future. He asked me, as a nephrologist with no conflict of interest, to write a report in one week.  I achieved this by sacrificing sleep and alcohol.”

(FDA  approval in the United States was eventually given in 2002; the FDA waiting for additional evidence from randomised controlled trials conducted in the United States (Wolfson M et al. AJKD 2002; 40:1055) before they were satisfied.)

 Once UK and European licences were obtained, ML Laboratories then offered icodextrin to Baxter Healthcare on very favourable financial terms, but Baxter declined. The senior medical staff within Baxter were not convinced icodextrin was a colloidal osmotic agent, despite the evidence presented to them.  ML then reached an agreement with Fresenius AG to collaborate in the field of PD. This agreement required a clinician wishing to prescribe icodextrin to use the Fresenius PD system, which at that time held only a minority of the UK PD market. The ML-Fresenius agreement did not last and was terminated in March 1996. Two months later, ML Laboratories granted an exclusive worldwide license to Baxter Healthcare , who paid a much larger sum than the offer they had previously turned down! (In 2005, ML Laboratories was acquired by Quadrant Technologies (as Innovata plc), and in 2007 this was taken over by Vectura Group plc.)

In discussions with Netar Mallick, Gerry Milner had agreed that the proceeds of the clinical application of icodextrin would be shared with the MRI Renal Unit. However this was not sufficiently well documented before Milner’s untimely death; neither ML laboratories nor the Milner family could trace evidence of the agreement. And in due course neither ML Laboratories nor Baxter were prepared to honour the arrangement for ‘appropriate compensation’ despite strenuous negotiation by Netar Mallick.

Thus an academic-industry collaboration which started so well between MRI and ML Laboratories turned out to undervalue the contribution of the clinicians and scientists who had done the crucial research and development work.


Icodextrin has now been in clinical use for more than 25 years and has been an important step forward in the use of PD. It is now used by many thousands of patients worldwide and in richer countries penetration probably exceeds 50%  of the PD market. 

The CAPD clinical team at MRI circa 1985 (courtesy of Linda Uttley)

Its success is undoubtedly attributable to its humble beginning in Manchester,  where a unique blend of highly motivated clinical medical and nursing  staff and thirty three loyal and courageous patients created a promise of a successful product and inspired the formation of a new pharmaceutical company, M L Laboratories Plc, which secured the necessary expertise and resources to complete the development of icodextrin.




Last Updated on May 23, 2023 by John Feehally