Icodextrin: Ten Years of Clinical Experience

Introduction

Icodextrin solution for peritoneal dialysis (PD) has profoundly changed prescription results and technique retention. The MIDAS study ten years ago has demonstrated that icodextrin produces sustained ultrafiltration in long dwells, due to the oncotic driving force of the isosmolar polymer [1]. The MIDAS study has also reported safety and tolerability of the solution in the long term. After this first trial many studies have been published reporting positive experiences and various side effects.

The early studies have well shown that the polymer has a slowly progressive but sustained ultrafiltration profile and low absorption [2]. As a consequence the first indication has been the CAPD overnight long dwell [1]. The MIDAS study has shown the efficacy and safety of icodextrin in long-term with dwell-time duration between 8 and 12 hours. The ultrafiltration was good with reduced fluid overload complications and hypertension compared with traditional glucose solutions and increased quality of life. On the other hand the absorption of the polymer showed to be significant with an increase of degradation fractions in plasma and in particular maltose. This undesired effect had no clinical consequences but limited the indication of the chronic use to only one 2-liter bag a day [1].

The sustained ultrafiltration of icodextrin showed good results during the daytime long dwell of CCPD as described in clinical reports [3-5]. Increasing ultrafiltration volume with icodextrin use, both in CAPD and APD, enhanced sodium removal together with solutes clearance [3, 4].

Icodextrin is indicated when residual renal function is ended and mantaining body fluid equilibrium is difficult with more hypertonic glucose solutions prescription. In these situations icodextrin can extend peritoneal dialysis retention and peritoneal membrane duration [6]. Moreover, when peritoneal function shows ultrafiltration failure due to aquaporin impaired function, icodextrin not only exerts unaltered efficient ultrafiltration rates but also allows membrane recovery associated with other non-glucose solutions [7].

Icodextrin can be used as overnight bag during acute bacterial peritonitis with the purpose to control body fluid in a clinical situation where glucose ultrafiltration is impaired [8]. The particular ultrafiltration mechanism of the polymer allows good results with the inflamed membrane. There are no reported problems of antibiotic compatibility and the iso-osmolality of the solution allows fast membrane recovery.

Icodextrin slow absorption and metabolism offers advantages in the field of dislipidemia and type 2 diabetes control. In fact the solution does not provoke glucose rise or stimulate insulin secretion during the dwell. This finding can be confirmed by the observation of hyperinsulinism reduction with chronic use of icodextrin in non-diabetic PD patients [9]. Other trials have confirmed the positive clinical experiences of MIDAS with improved ultrafiltration, enhanced clearances and good tolerability [10].

Icodextrin is a mixture of glucose polymers with a wide range of molecular weights. In human body the polymer is subjected to an absorption and degradation process that modifies the composition reducing gradually the dimensions of the various molecules and increasing markedly the concentration of the disaccaride maltose in plasma. As a consequence it is difficult to quantitate all these different and changing molecules in dialysis fluids and in plasma.

Chromatography and quantitation of all single molecule peaks is the elective method, and after the first experiences with gel migration now HPLC with ion-exchange or refractory index detectors is the method of choice. This method allows the exact determination of the molecular composition of icodextrin and maltose but it is slow and complex. A simpler method, based on the complete hydrolization of icodextrin by enzymatic hydrolysis, allows the accurate determination of total icodextrin mass in all biologic fluids. This method is fast, not expensive and can be used in all laboratories [11]. Testing this method in our laboratory against HPLC with refractory index detector gave good results in terms of total icodextrin assay both in dialysis fluid and plasma [12] and permitted the evaluation of the absorption of icodextrin from the peritoneal cavity and the recovery of the polymer in plasma. The absorption of icodextrin trough lymphatic and non-lymphatic pathways in dwell between 8 and 12 hours has been reported around 20% in MIDAS study, corresponding to 29±5 g of carbohydrate [1]. From our experimental data the total absorption of icodextrin in 10 patients was 17±9% at 4 hours, 27±11% at 8 hours, 34±11% at 12 hours and reached 40±11% at 16 hours [13].

Icodextrin in few cases do not produce the desired ultrafiltration and these patients can be defined as non-responders. In the MIDAS trial they are described in a small percentage [1] and another paper describes three cases [14]. We have studied 21 patients from three italian centers with reported low icodextrin ultrafiltration rates. The study was performed with a single 8 hours icodextrin dwell using intraperitoneal RISA tracer to monitor intraperitoneal volume, true lymphatic and non-lymphatic absorption. We were able to find only two patients with a clear pattern of negative ultrafiltration, both characterized by low peritoneal solute transport, normal true lymphatic absorption and abnormally high non-lymphatic absorption [15].

After absorption, icodextrin is subjected to a degradation that is shown by plasma metabolytes pattern with a fast decrease of bigger molecules and a corresponding increase of maltose. Analyzing the same metabolytes in dialysis fluid during the dwell we have found a pattern of increasing levels of small metabolytes with decreasing levels of bigger ones. These findings suggest a partial depolymerization of icodextrin also in dialysate during the dwell. However this phenomenon is quantitatively limited (5.8%) and does not influence significantly fluid osmolality [16, 17].

The problem of allergic reactions was well known since the release of the solution. These have been increasingly reported with the widening of clinical experience. The icodextrin allergies are generally described as skin rashes, blistering or exfoliative, reversible with icodextrin withdrawal and reproducible with solution rechallenge. The onset of the allergy is between 4 and 12 days of use and the reported incidence of the problem is between 2.5% and 15% of the treated patients [18, 19].

Another frequently reported problem related to icodextrin solution is sterile peritonitis. This type of peritonitis is characterized by negative cultures, positive leucocyte count, no abdominal pain, normal CRP levels and prompt recovery with icodextrin withdrawal without antibiotic therapy [20-23].

The biocompatibility of icodextrin should be better than standard solutions because the solution does not contain glucose and it is isosmolar to plasma. Chronic damage of peritoneum due to high glucose levels, like osmotic stress, mediators activation and glicosilation, can be reduced by icodextrin use [24]. This assumtion is corroborated by some positive in vitro and human studies [25, 26]. On the other hand, a group reported in animal experiments a mesothelial damage with icodextrin similar to glucose solutions [27, 28] and an in vivo study shows that there is no difference of glycation markers in the effluent between icodextrin and standard solutions [29].

In our center we have performed a single comparison between IL-6 levels in 2.27% glucose with bicarbonate-lactate buffer and 7.5% icodextrin solution drainages of two consecutive 8-hour overnight dwell in 12 chronic CAPD patients. Eight patients were chronic icodextrin users. Drainage volume was 2317±233 mL with 2.27% glucose and 2490±264 mL with icodextrin (p=0.021), dialysate IL-6 was 71±48 ng/mL with 2.27% glucose and 85±50 ng/mL with icodextrin (p=ns), the IL-6 excreted mass was 166±117 mcg with 2.27% glucose and 212±120 mcg with icodextrin (p=ns). IL-6 in plasma was below detection levels in all patients suggesting a local release of the mediator. These data, together with literature reports, show that icodextrin solution does not resolve all biocompatibility issues probably because it is acid, the heat sterilization process produces degradation compounds, plasticizers together with other undesirable substances are still present, and in all actual PD schedules icodextrin solution cannot replace completely glucose solution because it is limited to only one bag a day.

1. Mistry CD, Gokal R, Peers E. A randomized multicenter clinical trial comparing isosmolar icodextrin with hyperosmolar glucose solution in CAPD. MIDAS Study Group. Kidney Int 1994; 46: 496-503.

Part of the text and figures was presented at the International Vicenza PD Meeting 2003