A novel “bimodel” use of icodextrin peritoneal dialysis solutions

Kidney International, Vol. 53 (1998), pp. 1089 –1090

EDITORIAL

A novel “bimodal” use of icodextrin peritoneal dialysis solutions With current technology, most peritoneal dialysis (PD) patients can achieve the currently recommended minimal total solute clearance goals [1] if one individualizes the PD prescription [2]. However, in some cases, the maximal clearances that can be obtained practically are barely above these targets. In this issue of the journal, Douma et al [3] describe the first experience with the short-term use of peritoneal dialysis fluids containing both the glucose polymer (GP) icodextrin and nitroprusside (NP). Comparing GP alone to the GP/NP combination, they concluded that: (a) GP/NP solutions were well tolerated; (b) for long dwells (. 3 hours), transcapillary ultrafiltration (TCUF) was higher with the addition of NP; (c) net ultrafiltration (UF) after an 8 hour dwell was 49% higher with GP/NP; and (d) there was an increase in effective surface area and solute transport of all solutes (including albumin). What is their reasoning and its clinical significance? In PD, solute removal is dependent on dialysate flow (that is, drain volume), intrinsic peritoneal membrane (PM) permeability to solutes and the effective PM surface area. Maintenance of euvolemia has traditionally been an osmotically driven phenomenon via solutions made hypertonic to plasma using glucose as an osmotic agent, a form of “crystalloid” osmosis. Unfortunately, concurrent with the diffusion mediated transfer of solute from blood to dialysate, there is absorption of glucose from the peritoneum. Thus, during long dwells with glucose containing solutions, the osmotic gradient is quickly dissipated, ultrafiltration ceases and, unless the instilled fluid is drained, net fluid absorption via the peritoneal lymphatics predominates so that in some cases drain volume and solute clearances are not optimized. Hence, during long dwells, higher glucose concentrations and their inherent metabolic complications are used to maintain UF. With semipermeable membranes, osmotic flow is possible between solutions if there is a difference in the size of the sum of the products of the reflection coefficients and molar concentrations of solutes on each side of the membrane via “colloid” osmosis [4]. Icodextrin, a glucose polymer, isolated by hydrolyzed corn starch as a mixture of oligopolysaccharides has been shown to be an excellent “colloid” osmotic agent [5]. During PD, Icodextrin was associated with slow but sustained net ultrafiltration throughout the dwell. In a multicenter randomized study [6], it was shown that at 8 hours, UF with the polymer was similar to that with 3.86% glucose (4.25% dextrose), suggesting that Icodextrin was a safe and effective alternative osmotic agent which could poten-

Key words: clearance, dialysis, dialysate, transcapillary ultrafiltration, peritoneal membrane. Received for publication December 1, 1997 and in revised form December 8, 1997 Accepted for publication December 8, 1997

© 1998 by the International Society of Nephrology

tially replace hypertonic glucose for sustained UF during long dwells. Also significant is that GP solutions can be used as a vehicle for “bimodal” solution preparation such as the one in this study. For short dwells, net UF tends to be less than what can be achieved with the crystalloid induced UF from glucose containing solutions. Thus, combinations of “crystalloids” and “colloids” could be adjusted to achieve a wide range of UF profiles for any dwell time by adjusting the amount of small and large MW agents in the solution. Many other potentially beneficial additives to PD solutions (amino acids) are vasoactive. To maximize their effect, sustained UF is needed. Initial studies have already been done using GP combinations to explore these uses. Douma et al [3]. have attempted to capitalize on the sustained UF associated with GP. They found that by increasing the effective peritoneal membrane surface area by adding NP (discussed later) to GP containing solutions, that one could augment UF (from 344 mls to 540 mls) and increased solute clearances for urea by 13% and for creatinine, 19% during an 8 hour dwell. These changes could potentially increase weekly creatinine clearance for an average 1.73 m2 patient by about 5 liters/week. Based on the CANUSA study [7], this may decrease the predicted mortality by 7%. These 8-hour dwell UF/clearance data must be interpreted with some caution. First of all, many CAPD patients have a longer overnight dwell (9 or 10 hours). The daytime dwell for classic CCPD is 13 to 15 hours. Although the sustained UF with GP is likely to last for 14 to 16 hours, it is not known how long NP/GP can sustain the increased UF observed. The authors note that the D/P ratio of cGMP at 4 hours is higher than that after 8 hours. This is likely due to absorption of the locally generated cGMP from dialysate into the circulation, but could it also be due in part to decreased cGMP conversion? The effect of nitric oxide (NO) induced vasodilation is short. How sustained is the conversion to NO? Further studies are needed. The effective functional surface area is considerably less than the anatomical surface area and is primarily determined by the number of perfused capillaries which normally is only about 25%. NP is readily metabolized by endothelium to NO. In smooth muscles, NO then reacts with soluble guanylate cyclase resulting in increased intracellular concentrations of cGMP with resultant vascular relaxation, which increases peritoneal membrane surface area, resultant diffusion and potentially UF. NO is quickly oxidated to the stable inorganic nitrogen oxides, nitrite and nitrate. With standard fluids/dwells this effect is mitigated because of the associated increased glucose absorption [8]. Due to the sustained UF with GP, one can achieve the potential positive affect of adding NO. There are reasons to further explore this combination. It is uncertain if the human peritoneum normally produces NO. Data from this study are consistent with the hypothesis that NP is metabolized locally to NO which via cGMP causes vasodilatation

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Burkart: Editorial

and an increase in the effective PM surface area. What is not clear is how long does the effect last (in hours), and is it eventually sustained (months) or irreversible? If this increase in the effective surface area is sustained over a 24 hour period, would not the increased UF/clearance obtained by the GP/NP solution during the overnight dwell be mitigated by 1.36% glucose solutions (increased rapidity of glucose absorption) during the day? These data were not reported. One goal in the long-term patient is to prevent PM damage. One of the first signs of PM damage with glucose containing solutions is UF failure due to an increase in the effective surface area (increased D/P Cr). With GP solutions is this change beneficial, or is there a trade of for increased clearances/UF but potential long-term damage? This short-term study cannot resolve the possible concern about the increased albumin losses in the dialysate [9] and emerging data that suggest that rapid transporters have a higher relative risk of adverse outcome [10]. These questions need further evaluation and were not addressed in this study. In summary, although for the average patient, GP may only provide little clinically significant benefit over hypertonic glucose solutions as far as solute clearance is concerned, they are likely to allow one to obtain better blood pressure and volume control without the need for hypertonic glucose and its associated metabolic load. I command the authors for investigating further “bimodal” solutions. The GP/NP solutions will likely be a further benefit in promoting euvolemia and control of blood pressure in PD patients, while slightly augmenting solute clearance especially once RRF is lost. It is unknown what, if any, long-tern benefits GP or GP/NP will have on the peritoneal membrane. Further longterm studies are warranted. JOHN BURKART Winston-Salem, North Carolina, USA

Reprint requests to John Burkart, M.D., Bowman Gray School of Medicine, Section on Nephrology, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1053, USA.

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